title: Protein structure and the spandrels of San Marco: insulin's receptor-binding surface is buttressed by an invariant leucine essential for its stability.
abstract: Insulin provides a model of induced fit in macromolecular recognition: the hormone's conserved core is proposed to contribute to a novel receptor-binding surface. The core's evolutionary invariance, unusual among globular proteins, presumably reflects intertwined constraints of structure and function. To probe the architectural basis of such invariance, we have investigated hydrophobic substitutions of a key internal side chain (Leu(A16)). Although the variants exhibit perturbed structure and stability, moderate receptor-binding activities are retained. These observations suggest that the A16 side chain provides an essential structural buttress but unlike neighboring core side chains, does not itself contact the receptor. Among invertebrate insulin-like proteins, Leu(A16) and other putative core residues are not conserved, suggesting that the vertebrate packing scheme is not a general requirement of an insulin-like fold. We propose that conservation of Leu(A16) among vertebrate insulins and insulin-like growth factors is a side consequence of induced fit: alternative packing schemes are disallowed by lack of surrounding covariation within the hormone's hidden receptor-binding surface. An analogy is suggested between Leu(A16) and the spandrels of San Marco, tapering triangular spaces at the intersection of the dome's arches. This celebrated metaphor of Gould and Lewontin emphasizes the role of interlocking constraints in the evolution of biological structures.
authors.affiliation: Department of Biochemistry, Case Western Reserve School of Medicine, Cleveland, Ohio 44106-4935, USA. weiss@biochemistry.cwru.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Weiss
authors.forename: Satoe H
authors.initials: SH
authors.lastname: Nakagawa
authors.forename: Wenhua
authors.initials: W
authors.lastname: Jia
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Qing-xin
authors.initials: QX
authors.lastname: Hua
authors.forename: Ying-Chi
authors.initials: YC
authors.lastname: Chu
authors.forename: Run-ying
authors.initials: RY
authors.lastname: Wang
authors.forename: Panayotis G
authors.initials: PG
authors.lastname: Katsoyannis
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D004355:Drug Stability; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D007448:Invertebrates; D007930:Leucine; D008322:Mammals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011972:Receptor, Insulin / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014714:Vertebrates
chemical_list: D007328:Insulin; D011972:Receptor, Insulin; D007930:Leucine