HGNC Approved Gene Symbol: KIF16B
Cytogenetic location: 20p12.1 Genomic coordinates (GRCh38): 20:16,272,104-16,573,448 (from NCBI)
KIF16B is a kinesin that regulates the intracellular motility of early endosomes (Hoepfner et al., 2005). KIF16B mediates basolateral recycling of adaptor protein-1B (AP1B; see 600157) cargo, such as transferrin receptor (TFR, or TFRC; 190010), to apical recycling endosomes (AREs) in cells lacking AP1B (Perez Bay et al., 2013).
Hoepfner et al. (2005) cloned full-length human KIF16B from a HeLa cell cDNA library. The deduced 1,318-amino acid KIF16B protein has a calculated molecular mass of 152 kD. It has an N-terminal kinesin motor domain, followed by a stalk region containing a forkhead (see 601090) homology (FHA) domain, and a C-terminal phox (see 608512) homology (PX) domain. KIF16B belongs to the kinesin-3 family, and it shares 59% amino acid identity in the motor domain with human KIF1A (601255), its closest paralog. KIF16B has a higher coiled-coil propensity in its stalk region compared with other kinesin-3 proteins. The N-terminal catalytic domain and the presence of 4 conserved amino acids C-terminal to the alpha-6 helix suggest that KIF16B is a plus-end motor protein. Northern and Western blot analyses showed that KIF16B was widely expressed, including in brain, kidney, liver, intestine, placenta, leukocytes, heart, and skeletal muscle.
Using recombinant human KIF16B, Hoepfner et al. (2005) confirmed that KIF16B functioned as a plus end-directed motor. KIF16B localized to phosphatidylinositol-3-phosphate (PI3P)-positive early endosomes, bound PI3P via its PX domain, and mobilized PI3P-containing early endosomes along microtubules in a manner dependent on RAB5 (179512) and VPS34 (602609). Overexpression and knockdown experiments in HeLa cells confirmed that KIF16B transported early endosome in vivo, thereby governing their spatial distribution and efficient recycling of cargo to the cell surface. Overexpression of KIF16B in HeLa cells impaired sorting of cargo from early endosomes to the degradative pathway, whereas ablation of KIF16B produced the opposite phenotype of accelerated degradation, indicating that KIF16B regulates the transport of cargo from early to late endosomes and, consequently, cargo degradation.
Perez Bay et al. (2013) examined Ap1b-deficient epithelia and found that lack of Ap1b inhibited basolateral recycling of Tfr from common recycling endosomes (CREs), the site of Ab1b function, but promoted an alternative recycling route to transfer to AREs. The alternative recycling route was blocked by knockdown of Kif16b in Ap1b-deficient MDCK cells, demonstrating that transport of basolateral Tfr to AREs requires Kif16b. Further analysis showed that Kif16b mediated trafficking of Tfr from CREs to AREs in Ap1b-deficient MDCK cells using noncentrosomal microtubules emerging from the Golgi complex.
Blatner et al. (2007) found that the PX domain of KIF16B (KIF16B-PX) bound PI3P-containing vesicles with high affinity and specificity, helping KIF16B translocate and tightly bind to early endosomes. The authors solved the X-ray crystal structure structure of KIF16B-PX to 2.2-angstrom resolution. The structure showed that KIF16B-PX consists of a twisted 3-stranded beta sheet flanked along its length by an alpha helix and a polyproline helix-containing loop, with a second helix filling the hollow of the concave structure. KIF16B-PX contains 2 small hydrophobic pockets and a pair of hydrophobic residues, L1248 and F1249, that sit in one of these pockets and are unique among PX domain structures and other lipid-binding domains. Further investigation demonstrated that L1248 and F1249 effectively penetrate the membrane, thereby providing extra membrane binding energy necessary for KIF16B-PX to stay on the membrane for an elongated period. Cationic residues within KIF16B-PX appeared to be involved in nonspecific membrane adsorption rather than specific PI recognition. However, the crystal structure suggested the presence of multiple cationic residues in and around the lipid-binding pocket of KIF16B, providing the membrane-binding surface of KIF16B with a strong positive electrostatic potential surrounding the hydrophobic side chains of L1248 and F1249 in the absence of PI3P. This positive potential, while promoting initial binding of the protein to the anionic membrane surface, interferes with membrane penetration of L1248 and F1249, because the process involves energetically unfavorable dehydration. Binding of PI3P to the pocket reduces the positive electrostatic potential near the hydrophobic residues, allowing their side chains to be exposed over the electrostatic potential barrier and leading to the enhanced penetration of the hydrophobic side chains into the membrane. Expression and localization analyses in A431 and HEK293 cells corroborated the notion that the uniquely exposed hydrophobic residues of KIF16B-PX are a key structural determinant of KIF16B cellular endosomal anchoring.
Gross (2018) mapped the KIF16B gene to chromosome 20p12.1 based on an alignment of the KIF16B sequence (GenBank AY166853) with the genomic sequence (GRCh38).
For discussion of a possible association between severely impaired intellectual development with microcephaly and variation in the KIF16B gene, see 618171.0001.
This variant is classified as a variant of unknown significance because its contribution to severely impaired intellectual development with microcephaly has not been confirmed.
In 2 brothers with severely impaired intellectual development and acquired microcephaly from a consanguineous Saudi family, Alsahli et al. (2018) detected a homozygous c.3611T-G transversion (c.3611T-G, NM_024704.4) in the KIF16B gene that resulted in a phe1204-to-cys (F1204C) substitution. The older brother was born at term with average birth parameters and with hypospadias and chordee. At 6 months developmental delay was noted, and at 9 months he developed generalized tonic-clonic seizures that were difficult to control. At age 6 years, he did not track or hold his bottle. Physical exam was notable for microcephaly (less than 1st percentile) and brachycephaly. Brain MRI showed diffuse white matter volume loss in the centrum semiovale and corona radiata regions with ex vacuo dilation of the lateral ventricles. EEG showed continuous spike, polyspike, and wave epileptic discharges in the bilateral occipital region. The younger brother was born at term with average parameters and at 6 months was noted to have developmental delay; his mother reported hypotonia since birth. He sat at 18 months and at 24 months had no additional gross motor skills. He could coo and smile but did not recognize his parents. Physical exam showed microcephaly (less than 1st percentile) and brachycephaly and was otherwise unremarkable. He did not have seizures. Routine chemistry and metabolic evaluation were unremarkable except for persistent mild elevation of total and direct bilirubin and alkaline phosphatase in the older brother. Whole-exome sequencing revealed variants in MPEG1 (610390), AFMID (arylformamidase), RIN2 (610222), FBXW2 (609071), and KIF16B. Mutation in the RIN2 gene causes a discordant phenotype. Only the KIF16B F1204C variant was found in homozygosity and segregated with the phenotype in the family. The F1204 residue is part of the hydrophobic core of the C-terminal PX domain, and mutation to cysteine was predicted to be highly disruptive to the structure and function of the KIF16B protein. The variant was not present in gnomAD or the Saudi Human Genome Program (SHGP). Functional studies were not performed.
Alsahli, S., Arold, S. T., Alfares, A., Alhaddad, B., Al Balwi, M., Kamsteeg, E. J., Al-Twaijri, W., Alfadhel, M. KIF16B is a candidate gene for a novel autosomal-recessive intellectual disability syndrome. Am. J. Med. Genet. 176A: 1602-1609, 2018. [PubMed: 29736960] [Full Text: https://doi.org/10.1002/ajmg.a.38723]
Blatner, N. R., Wilson, M. I., Lei, C., Hong, W., Murray, D., Williams, R. L., Cho, W. The structural basis of novel endosome anchoring activity of KIF16B kinesin. EMBO J. 26: 3709-3719, 2007. [PubMed: 17641687] [Full Text: https://doi.org/10.1038/sj.emboj.7601800]
Gross, M. B. Personal Communication. Baltimore, Md. 10/31/2018.
Hoepfner, S., Severin, F., Cabezas, A., Habermann, B., Runge, A., Gillooly, D., Stenmark, H., Zerial, M. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121: 437-450, 2005. [PubMed: 15882625] [Full Text: https://doi.org/10.1016/j.cell.2005.02.017]
Perez Bay, A. E., Schreiner, R., Mazzoni, F., Carvajal-Gonzalez, J. M., Gravotta, D., Perret, E., Lehmann Mantaras, G., Zhu, Y.-S., Rodriguez-Boulan, E. J. The kinesin KIF16B mediates apical transcytosis of transferrin receptor in AP-1B-deficient epithelia. EMBO J. 32: 2125-2139, 2013. [PubMed: 23749212] [Full Text: https://doi.org/10.1038/emboj.2013.130]