EF-hand, extracellular calcium-binding (EC) motif, found in testican-2 (TICN2); TICN2, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2 (Spock2), is an extracellular heparan sulphate proteoglycan expressed in brain, lung, and testis. It inhibits neurite extension from cultured primary cerebellar neurons and may play regulatory roles in the development of the central nervous system. It also participates in diverse steps of neurogenesis. Moreover, TICN2 may contribute to ECM remodeling by regulating function(s) of other testican family members, which possess membrane-type matrix metalloproteinases (MT-MMPs) inhibitory function. Furthermore, TICN2 corresponding gene SPOCK2 acts as a susceptibility gene for bronchopulmonary dysplasia. TICN2 contains an N-terminal signal peptide, a testican-specific domain followed by a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, a thyroglobulin-like domain (TY), and a C-terminal region with two putative glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr292 in the +Y position of EF-hand 2 in TICN2 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDWFQLLHENAKQNSSGSTGASPVNVLDKSLVASCKDSIGWMFSKLDTNGDLFLDQTELAAINLDKY 423
Cdd:cd16238    1 CTGQDLADLGDRLRDWFQLLHENSKQNGSGSPPASPASALDRSLVASCKDSIGWMFSKLDTSGDLFLDQAELAAINLDKY 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 975096486 424 EICIRPFFNSCDTYKDGRVSTAEWCFCFWREK 455
Cdd:cd16238   81 EVCIRPFFNSCDTYRDGRVSTAEWCFCFWREK 112

Thyroglobulin type-1 repeat; Thyroglobulin type 1 repeats are thought to be involved in the control of proteolytic degradation. The domain usually contains six conserved cysteines. These form three disulphide bridges. Cysteines 1 pairs with 2, 3 with 4 and 5 with 6.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 975096486  458 CLVELERIQIQEAAKKKP-GVFIPSCDEDGYYRKMQCDPGSGECWCVDHLGMELTGTR-MHGTPDC 521
Cdd:pfam00086   1 CERERARALEQAASGRPAsGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRtRGGDPDC 66

EF-hand, extracellular calcium-binding (EC) motif, found in testican-2 (TICN2); TICN2, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2 (Spock2), is an extracellular heparan sulphate proteoglycan expressed in brain, lung, and testis. It inhibits neurite extension from cultured primary cerebellar neurons and may play regulatory roles in the development of the central nervous system. It also participates in diverse steps of neurogenesis. Moreover, TICN2 may contribute to ECM remodeling by regulating function(s) of other testican family members, which possess membrane-type matrix metalloproteinases (MT-MMPs) inhibitory function. Furthermore, TICN2 corresponding gene SPOCK2 acts as a susceptibility gene for bronchopulmonary dysplasia. TICN2 contains an N-terminal signal peptide, a testican-specific domain followed by a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, a thyroglobulin-like domain (TY), and a C-terminal region with two putative glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr292 in the +Y position of EF-hand 2 in TICN2 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDWFQLLHENAKQNSSGSTGASPVNVLDKSLVASCKDSIGWMFSKLDTNGDLFLDQTELAAINLDKY 423
Cdd:cd16238    1 CTGQDLADLGDRLRDWFQLLHENSKQNGSGSPPASPASALDRSLVASCKDSIGWMFSKLDTSGDLFLDQAELAAINLDKY 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 975096486 424 EICIRPFFNSCDTYKDGRVSTAEWCFCFWREK 455
Cdd:cd16238   81 EVCIRPFFNSCDTYRDGRVSTAEWCFCFWREK 112

DIRS1 family of RNase HI in long-term repeat retroelements; Ribonuclease H (RNase H) enzymes are divided into two major families, Type 1 and Type 2, based on amino acid sequence similarities and biochemical properties. RNase H is an endonuclease that cleaves the RNA strand of an RNA/DNA hybrid in a sequence non-specific manner in the presence of divalent cations. RNase H is widely present in various organisms, including bacteria, archaea and eukaryotes. RNase HI has also been observed as adjunct domains to the reverse transcriptase gene in retroviruses, in long-term repeat (LTR)-bearing retrotransposons and non-LTR retrotransposons. RNase HI in LTR retrotransposons perform degradation of the original RNA template, generation of a polypurine tract (the primer for plus-strand DNA synthesis), and final removal of RNA primers from newly synthesized minus and plus strands. The catalytic residues for RNase H enzymatic activity, three aspartatic acids and one glutamic acid residue (DEDD), are unvaried across all RNase H domains. Phylogenetic patterns of RNase HI of LTR retroelements is classified into five major families, Ty3/Gypsy, Ty1/Copia, Bel/Pao, DIRS1 and the vertebrate retroviruses. The structural features of DIRS1-group elements are different from typical LTR elements. RNase H inhibitors have been explored as an anti-HIV drug target because RNase H inactivation inhibits reverse transcription.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486  39 CGHLIAQGKWSPQQASHSINWLELRAVSLALRASHQHMQDQHLLVRTDNMSTKAHINRQGGTRSKSLFKESRILLQWAEQ 118
Cdd:cd09275   15 LLNSRAHGPWSADERNKHINLLELKAVLLALQHFAAELKNRKILIRTDNTTAVAYINKQGGTSSPPLLALARQILLWCEQ 94

                         90       100
                 ....*....|....*....|....*.
gi 975096486 119 YTLSLRAEHLRGLSNQQADWLSRENL 144
Cdd:cd09275   95 RNIWLRASHIPGVLNTEADRLSRLGL 120

Thyroglobulin type I repeats.; The N-terminal region of human thyroglobulin contains 11 type-1 repeats TY repeats are proposed to be inhibitors of cysteine proteases

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 975096486 457 PCLVELERIQIQEAAKKKPGVFIPSCDEDGYYRKMQCDPGSGECWCVDHLGMELTGTRMHGT-PDC 521
Cdd:cd00191    1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTRGGpPNC 66

Kazal type serine protease inhibitors; Kazal type serine protease inhibitors and follistatin-like domains.

                           10        20        30
                   ....*....|....*....|....*....|....
gi 975096486   292 VCGSDGHTYSSVCKLEQQACLTSKQLTVKCEGQC 325
Cdd:smart00280  13 VCGSDGVTYSNECHLCKAACESGKSIEVKHDGPC 46

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

                         10        20        30
                 ....*....|....*....|....*....|....
gi 975096486 292 VCGSDGHTYSSVCKLEQQACLTSKQLTVKCEGQC 325
Cdd:cd00104    8 VCGSDGKTYSNECHLGCAACRSGRSITVAHNGPC 41

EF-hand, extracellular calcium-binding (EC) motif, found in testican-2 (TICN2); TICN2, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2 (Spock2), is an extracellular heparan sulphate proteoglycan expressed in brain, lung, and testis. It inhibits neurite extension from cultured primary cerebellar neurons and may play regulatory roles in the development of the central nervous system. It also participates in diverse steps of neurogenesis. Moreover, TICN2 may contribute to ECM remodeling by regulating function(s) of other testican family members, which possess membrane-type matrix metalloproteinases (MT-MMPs) inhibitory function. Furthermore, TICN2 corresponding gene SPOCK2 acts as a susceptibility gene for bronchopulmonary dysplasia. TICN2 contains an N-terminal signal peptide, a testican-specific domain followed by a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, a thyroglobulin-like domain (TY), and a C-terminal region with two putative glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr292 in the +Y position of EF-hand 2 in TICN2 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDWFQLLHENAKQNSSGSTGASPVNVLDKSLVASCKDSIGWMFSKLDTNGDLFLDQTELAAINLDKY 423
Cdd:cd16238    1 CTGQDLADLGDRLRDWFQLLHENSKQNGSGSPPASPASALDRSLVASCKDSIGWMFSKLDTSGDLFLDQAELAAINLDKY 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 975096486 424 EICIRPFFNSCDTYKDGRVSTAEWCFCFWREK 455
Cdd:cd16238   81 EVCIRPFFNSCDTYRDGRVSTAEWCFCFWREK 112

EF-hand, extracellular calcium-binding (EC) motif, found in testican-1 (TICN1); TICN1, also termed protein SPOCK, or SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 1 (Spock1), is a secreted chimeric proteoglycan that is highly expressed in brain and carries both chondroitin and heparan sulfate glycosaminoglycan side chains. It promotes resistance against Pseudomonas aeruginosa-induced keratitis through regulation of matrix metalloproteinase (MMP)-2 expression and activation. It also acts as a potential cancer prognostic marker that promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/Akt pathway. Moreover, TICN1 corresponding gene SPOCK1 is a novel transforming growth factor-beta target gene that regulates lung cancer cell epithelial-mesenchymal transition. It is also up-regulated by chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L), and promotes human hepatocellular carcinoma (HCC) cell invasiveness and metastasis. Furthermore, TICN1 inhibits the lysosomal cysteine protease cathepsin L in intracellular vesicles and in the extracellular milieu. TICN1 contains an N-terminal signal sequence known to direct nascent polypeptides to the extracellular space, an unique region to the testicans, a follistatin (FS)-like domain generally involving five disulfide bridges, an extracellular calcium-binding (EC) domain including a pair of EF hands, and a thyroglobulin type-1 (TY) domain followed by a C-terminal acidic region with high density of negatively charged amino acids. The substitution of a ligating Asp residue by Phe291 in the +Y position of EF-hand 2 in TICN1 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDWFQLLHENAKQNSSGSTGASPVNVLDKSLVASCKDSIGWMFSKLDTNGDLFLDQTELAAINLDKY 423
Cdd:cd16237    1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDKY 80

                         90       100       110
                 ....*....|....*....|....*....|...
gi 975096486 424 EICIRPFFNSCDTYKDGRVSTAEWCFCFwrEKP 456
Cdd:cd16237   81 EPCMKPLFNSCDSFKDGKLSNNEWCYCF--QKP 111

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDWFQLLHENAKQNSSGSTGAspvnvLDKSLVASCKDSIGWMFSKLDTNGDLFLDQTELAAINLD-- 421
Cdd:cd00252    1 CPGSELMQFPDRLLDWLLLLKEQDENRSYDNNKR-----GHDLSGTMRKEIAQWEFDNLDNNKDGKLDKRELAPFRAPlm 75

                         90       100       110
                 ....*....|....*....|....*....|..
gi 975096486 422 KYEICIRPFFNSCDTYKDGRVSTAEWCFCFWR 453
Cdd:cd00252   76 PLEHCARGFFESCDLNKDKKISLQEWLGCFGV 107

DIRS1 family of RNase HI in long-term repeat retroelements; Ribonuclease H (RNase H) enzymes are divided into two major families, Type 1 and Type 2, based on amino acid sequence similarities and biochemical properties. RNase H is an endonuclease that cleaves the RNA strand of an RNA/DNA hybrid in a sequence non-specific manner in the presence of divalent cations. RNase H is widely present in various organisms, including bacteria, archaea and eukaryotes. RNase HI has also been observed as adjunct domains to the reverse transcriptase gene in retroviruses, in long-term repeat (LTR)-bearing retrotransposons and non-LTR retrotransposons. RNase HI in LTR retrotransposons perform degradation of the original RNA template, generation of a polypurine tract (the primer for plus-strand DNA synthesis), and final removal of RNA primers from newly synthesized minus and plus strands. The catalytic residues for RNase H enzymatic activity, three aspartatic acids and one glutamic acid residue (DEDD), are unvaried across all RNase H domains. Phylogenetic patterns of RNase HI of LTR retroelements is classified into five major families, Ty3/Gypsy, Ty1/Copia, Bel/Pao, DIRS1 and the vertebrate retroviruses. The structural features of DIRS1-group elements are different from typical LTR elements. RNase H inhibitors have been explored as an anti-HIV drug target because RNase H inactivation inhibits reverse transcription.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486  39 CGHLIAQGKWSPQQASHSINWLELRAVSLALRASHQHMQDQHLLVRTDNMSTKAHINRQGGTRSKSLFKESRILLQWAEQ 118
Cdd:cd09275   15 LLNSRAHGPWSADERNKHINLLELKAVLLALQHFAAELKNRKILIRTDNTTAVAYINKQGGTSSPPLLALARQILLWCEQ 94

                         90       100
                 ....*....|....*....|....*.
gi 975096486 119 YTLSLRAEHLRGLSNQQADWLSRENL 144
Cdd:cd09275   95 RNIWLRASHIPGVLNTEADRLSRLGL 120

Thyroglobulin type I repeats.; The N-terminal region of human thyroglobulin contains 11 type-1 repeats TY repeats are proposed to be inhibitors of cysteine proteases

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 975096486 457 PCLVELERIQIQEAAKKKPGVFIPSCDEDGYYRKMQCDPGSGECWCVDHLGMELTGTRMHGT-PDC 521
Cdd:cd00191    1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTRGGpPNC 66

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC) and similar proteins; This family includes secreted protein acidic and rich in cysteine (SPARC), secreted protein, acidic and rich in cysteine-like 1 (SPARCL1), and similar proteins. SPARC is a prototypic collagen-binding matricellular protein that is involved in extracellular matrix (ECM) assembly and fibrosis through binding both fibrillar collagen and basal lamina collagen IV. It regulates the activity of matrix metalloproteinases (MMPs), as well as the growth factor signaling mediated by cell surface receptors including vascular endothelial growth factor (VEGF) receptor, basic fibroblast growth factor (bFGF), and transforming growth factor (TGF) beta1. It also shows survival activity in tumor progression. SPARC contains an N-terminal acidic 52-residue segment followed by a follistatin-like (FS) domain, and an alpha-helical EC domain with 2 unusual calcium-binding EF-hands and the collagen-binding site. SPARCL1 is the closest family member to SPARC. It shares the three primary domains contained within SPARC with an expanded N-terminal domain. SPARCL1 may function as both a tumor suppressor and as a regulator of angiogenesis. It can bind to collagens and be counter-adhesive to wild-type dermal fibroblasts, but do not influence rates of cell proliferation. Moreover, SPARCL1 can influence central nervous system (CNS) development and synaptic rearrangement.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDW-FQLLHENAKQNSSGStgaspvNVLDKSLVASCKDS------IGWMFSKLDTN-GDLFLDQTEL 415
Cdd:cd16231    1 CLDEELSEFPLRMRDWlKNVMVQLAERDELHE------GLTEKELEDFQKNYkmyvypVHWKFCDLDQHpHDRYLSHHEL 74

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 975096486 416 AAIN--LDKYEICIRPFFNSCDTYKDGRVSTAEWCFCF 451
Cdd:cd16231   75 APLRapLVPMEHCTTPFLETCDADNDKLISLKEWGACL 112

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 975096486  281 CKPCHMTQLASVCGSDGHTYSSVCKLEQQACLTSKQL---TVKCEGQC 325
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVkeeKVKYDGSC 50

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1); SPARCL1, also termed SPARC-like protein 1, or high endothelial venule protein (Hevin), or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2, is a diversely expressed and developmentally regulated extracellular matrix glycoprotein involved in tissue repair and remodeling via interaction with the surrounding extracellular matrix (ECM) proteins. It plays a pivotal role in the corneal wound healing. SPARCL1 may function as both a tumor suppressor and as a regulator of angiogenesis. It regulates cell migration/invasion and suppresses metastasis in many cancers, including prostate cancer, colorectal cancer, gastric cancer, and breast cancer. It can bind to collagens and be counter-adhesive to wild-type dermal fibroblasts, but do not influence rates of cell proliferation. Moreover, SPARCL1 contributes to neural development and participates in remodeling events associated with neuronal degeneration following neural injury. It can influence central nervous system (CNS) development and synaptic rearrangement. SPARCL1 is the closest family member to secreted protein acidic and rich in cysteine (SPARC), but does not compensate for the absence of SPARC in the CNS. SPARC contains an N-terminal acidic 52-residue segment followed by a follistatin-like (FS) domain, and an alpha-helical EC domain with 2 unusual calcium-binding EF-hands and the collagen-binding site. SPARCL1 shares the three primary domains contained within SPARC with an expanded N-terminal domain.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 395 IGWMFSKLDTN-GDLFLDQTELAAI--NLDKYEICIRPFFNSCDTYKDGRVSTAEWCFCF 451
Cdd:cd16236   30 VHWQFAQLDQHpSDRFLTHSELAPLraSLVPMEHCITRFFQECDADKDKLITLKEWCHCF 89

Ty3/Gypsy family of RNase HI in long-term repeat retroelements; Ribonuclease H (RNase H) enzymes are divided into two major families, Type 1 and Type 2, based on amino acid sequence similarities and biochemical properties. RNase H is an endonuclease that cleaves the RNA strand of an RNA/DNA hybrid in a sequence non-specific manner in the presence of divalent cations. RNase H is widely present in various organisms, including bacteria, archaea and eukaryotes. RNase HI has also been observed as adjunct domains to the reverse transcriptase gene in retroviruses, in long-term repeat (LTR)-bearing retrotransposons and non-LTR retrotransposons. RNase HI in LTR retrotransposons perform degradation of the original RNA template, generation of a polypurine tract (the primer for plus-strand DNA synthesis), and final removal of RNA primers from newly synthesized minus and plus strands. The catalytic residues for RNase H enzymatic activity, three aspartatic acids and one glutamic acid residue (DEDD), are unvaried across all RNase H domains. Phylogenetic patterns of RNase HI of LTR retroelements is classified into five major families, Ty3/Gypsy, Ty1/Copia, Bel/Pao, DIRS1 and the vertebrate retroviruses. Ty3/Gypsy family widely distributed among the genomes of plants, fungi and animals. RNase H inhibitors have been explored as an anti-HIV drug target because RNase H inactivation inhibits reverse transcription.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486  40 GHLIA--QGKWSPQQASHSINWLELRAVSLALRASHQHMQDQHLLVRTDNMSTKaHINRQggtrsKSLfkeSRILLQWAE 117
Cdd:cd09274   24 ERPIAffSRKLTPAERNYSTTEKELLAIVWALKKFRHYLLGRPFTVYTDHKALK-YLLTQ-----KDL---NGRLARWLL 94

                         90       100
                 ....*....|....*....|....*..
gi 975096486 118 ---QYTLSLraEHLRGLSNQQADWLSR 141
Cdd:cd09274   95 llsEFDFEI--EYRPGKENVVADALSR 119

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC); SPARC, also termed basement-membrane protein 40 (BM-40), or osteonectin (ON), is a prototypic collagen-binding matricellular protein that is essential for embryo development in invertebrates and highly expressed in bone. It participates in normal tissue remodeling as it regulates the deposition of extracellular matrix, as well as in neoplastic transformation. It is involved in extracellular matrix (ECM) assembly and fibrosis through binding both fibrillar collagen and basal lamina collagen IV. It regulates the activity of matrix metalloproteinases (MMPs), as well as the growth factor signaling mediated by cell surface receptors including vascular endothelial growth factor (VEGF) receptor, basic fibroblast growth factor (bFGF), and transforming growth factor (TGF) beta1. SPARC shows survival activity in tumor progression. It plays a role in metastatic process to the lung during melanoma progression. It can suppress prostate cancer cell growth and survival. Moreover, SPARC is a bone- associated protein that has a major role in bone development and mineralisationis. It is involved in the initiation and progression of vascular calcification and upregulated by adiponectin. Furthermore, SPARC may be one of the molecules that govern the uptake and delivery of proteins from blood to the cerebrospinal fluid (CSF) during brain development. SPARC contains an N-terminal acidic 52-residue segment followed by a follistatin-like (FS) domain, and an alpha-helical EC domain with 2 unusual calcium-binding EF-hands and the collagen-binding site. Platelet-derived growth factor (PDGF) also interacts with its EC domain, but in a calcium-independent manner, whereas collagen binding is calcium-dependent.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486 344 CTGQDLADLGDRLRDWFQllhenakqnssgstgaspvNVLDKSLVASCKDSIGWMFSKLDTNG-DLFLDQTELAAIN--L 420
Cdd:cd16235    1 CLDSELTEFPLRMRDWLK-------------------NVLVTLYERDYIFPVHWQFGQLDQHPiDGYLSHTELAPLRapL 61

                         90       100       110
                 ....*....|....*....|....*....|.
gi 975096486 421 DKYEICIRPFFNSCDTYKDGRVSTAEWCFCF 451
Cdd:cd16235   62 IPMEHCTTRFFETCDLDNDKYIALDEWAGCF 92

Ribonuclease H-like superfamily, including RNase H, HI, HII, HIII, and RNase-like domain IV of spliceosomal protein Prp8; Ribonuclease H (RNase H) enzymes are divided into two major families, Type 1 and Type 2, based on amino acid sequence similarities and biochemical properties. RNase H is an endonuclease that cleaves the RNA strand of an RNA/DNA hybrid in a sequence non-specific manner in the presence of divalent cations. It is widely present in various organisms, including bacteria, archaea, and eukaryotes. Most prokaryotic and eukaryotic genomes contain multiple RNase H genes. Despite the lack of amino acid sequence homology, type 1 and type 2 RNase H share a main-chain fold and steric configurations of the four acidic active-site residues and have the same catalytic mechanism and functions in cells. RNase H is involved in DNA replication, repair and transcription. An important RNase H function is to remove Okazaki fragments during DNA replication. RNase H inhibitors have been explored as anti-HIV drug targets since RNase H inactivation inhibits reverse transcription. This model also includes the Prp8 domain IV, which adopts the RNase fold but shows low sequence homology; domain IV is implicated in key spliceosomal interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486  55 HSINWLELRAVSLALR-ASHQHMqdQHLLVRTDNMSTKAHINRQGGTRSKSLFKESRILLQWAEQYTLSLraEHLRGLSN 133
Cdd:cd06222   38 PTALEAELLALLLALElALDLGY--LKVIIESDSKYVVDLINSGSFKWSPNILLIEDILLLLSRFWSVKI--SHVPREGN 113

                 ....*...
gi 975096486 134 QQADWLSR 141
Cdd:cd06222  114 QVADALAK 121

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 975096486  392 KDSIGWMFSKLDTNGDLFLDQTELA--------AINLDKYEicIRPFFNSCDTYKDGRVS 443
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKkllrkleeGEPLSDEE--VEELFKEFDLDKDGRIS 58