ISMB99 - Tutorial 8

 


Sequence-structure relationships and evolutionary structure changes in proteins

Arthur Lesk

Within the broad biochemical unity of life on Earth there is at the molecular level also a great diversity. This has been brought into its sharpest focus by studies of the relationships among nucleotide sequences of genes, amino acid sequences of proteins, and the three-dimensional structures and functions of proteins. The primary events in the generation of biological diversity are the mutation, insertion, and deletion of nucleotides in DNA sequences, or the larger-scale transposition of pieces of genetic material. Selection reacts to protein function as determined by protein structure.

Examination of homologous genes and proteins in different species have shown that evolutionary variation and divergence occur very generally at the molecular level. Proteins from related species have similar but not identical amino acid sequences. These sequences determine similar but not identical protein structures. In both closely and distantly related proteins the general response to mutation is conformational change. A core of the structure retains the same qualititative fold, whereas other parts of the structure may change conformation radically. The common core generally contains the major elements of secondary structure and peptides flanking them, including active site peptides. The nature of the forces that stabilize protein structures sets general limitations on conformational changes; other constraints derived from function vary from case to case. The maintenance of function in widely divergent sequences requires the integration of the response to mutations over all or at least a large portion of the molecule.

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