Protein folding and protein evolution: common folding nucleus in different subfamilies of c-type cytochromes?
Amino acid sequences of seven subfamilies of cytochromes c (mitochondrial cytochromes c, c1; chloroplast cytochromes c6, cf; bacterial cytochromes c2, c550, c551; in total 164 sequences) have been compared. Despite extensive homology within eukaryotic subfamilies, homology between different subfamilies is very weak. Other than the three heme-binding residues (Cys13, Cys14, His18, in numeration of horse cytochrome c) there are only four positions which are conserved in all subfamilies: Gly/Ala6, Phe/Tyr10, Leu/Val/Phe94 and Tyr/Trp/Phe97. In all 17 cytochromes c with known 3D-structures, these residues form a network of conserved contacts (6-94, 6-97, 10-94, 10-97 and 94-97). Especially strong is the contact between aromatic groups in positions 10 and 97, which corresponds to 13 interatomic contacts. As residues 6, 10 and residues 94, 97 are in (i, i+4) and (i, i+3) positions in the N and C-terminal helices, respectively, the above mentioned system of conserved contacts consists mainly of contacts between one turn of N-terminal helix and one turn of C-terminal helix. The importance of the contacts between interfaces of these helices has been confirmed by the existence of these contacts in both equilibrium and kinetic molten globule-like folding intermediates, as well as by mutational evidence that these contacts are involved in tight packing between the N and C-helices. Since these four residues are not involved in heme binding and have no other apparent functional role, their conservation in highly diverged cytochromes c suggests that they are of a critical importance for protein folding. The author assumes that they are involved in a common folding nucleus of all subfamilies of c-type cytochromes.
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Laboratory of Experimental and Computational Biology National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5677, USA.
D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D001665:Binding Sites; D002736:Chloroplasts / Q000378:metabolism; D017124:Conserved Sequence; D003574:Cytochrome c Group / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D006418:Heme / Q000378:metabolism; D006736:Horses; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D003574:Cytochrome c Group; D006418:Heme