Structural plasticity underpins promiscuous binding of the prosurvival protein A1

Callum Smits; Peter E Czabotar; Mark G Hinds; Catherine L Day

doi:10.1016/j.str.2008.02.009

Structural plasticity underpins promiscuous binding of the prosurvival protein A1

Structure. 2008 May;16(5):818-29. doi: 10.1016/j.str.2008.02.009.

Authors

Callum Smits¹, Peter E Czabotar, Mark G Hinds, Catherine L Day

Affiliation

¹ Biochemistry Department, University of Otago, Dunedin 9054, New Zealand.

PMID: 18462686
DOI: 10.1016/j.str.2008.02.009

Abstract

Apoptotic pathways are regulated by protein-protein interactions. Interaction of the BH3 domains of proapoptotic Bcl-2 family proteins with the hydrophobic groove of prosurvival proteins is critical. Whereas some BH3 domains bind in a promiscuous manner, others exhibit considerable selectivity and the sequence characteristics that distinguish these activities are unclear. In this study, crystal structures of complexes between the prosurvival protein A1 and the BH3 domains from Puma, Bmf, Bak, and Bid have been solved. The structure of A1 is similar to that of other prosurvival proteins, although features, such as an acidic patch in the binding groove, may allow specific therapeutic modulation of apoptosis. Significant conformational plasticity was observed in the intermolecular interactions and these differences explain some of the variation in affinity. This study, in combination with published data, suggests that interactions between conserved residues demarcate optimal binding.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amino Acid Substitution
Animals
Apoptosis Regulatory Proteins / chemistry*
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / isolation & purification
Apoptosis Regulatory Proteins / metabolism*
BH3 Interacting Domain Death Agonist Protein / chemistry
BH3 Interacting Domain Death Agonist Protein / metabolism
Crystallography, X-Ray
Glutathione Transferase / metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Mice
Models, Molecular
Molecular Sequence Data
Proline / metabolism
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / isolation & purification
Recombinant Fusion Proteins / metabolism
Sequence Homology, Amino Acid
Solubility

Substances

Apoptosis Regulatory Proteins
BH3 Interacting Domain Death Agonist Protein
Recombinant Fusion Proteins
Proline
Glutathione Transferase

Associated data

PDB/2VOF
PDB/2VOG
PDB/2VOH
PDB/2VOI