STRUCTURAL DIVERSITY IN A FAMILY OF HOMOLOGOUS PROTEINS

An interesting example of a structurally diverse group of sequentially homologous proteins is analyzed at the level of molecular interaction s. In this family, the EF-hand calcium-binding proteins, there are exa mples of at least three distinct mutual positions of the N and C-termi nal domains, despite significant sequence homology between all members of this family. Why does a particular protein choose one arrangement over another? To answer this question, detailed models of all proteins in their native structures as well as all alternative sequence/struct ure combinations are built by comparative modeling. By studying and co mparing interactions stabilizing native structures and destabilizing a lternative conformations, it is possible to gain insight into how such conformational diversity is achieved. It is shown that some mechanism s used to achieve it are: correlated mutations on the surface of two u nits and the presence of additional domains/chain fragments stabilizin g desired topologies. The implications of these findings, both for str ucture predictions for other members of this family, as well as the ge neral problem of quaternary structure formation, are discussed. (C) 19 96 Academic Press Limited