A thing of beauty: Structure and function of insulin's "aromatic triplet"
Author(s)
Weiss, MA; Lawrence, MC;
Journal Title
Diabetes Obesity & Metabolism
Publication Type
Journal Article
Abstract
The classical crystal structure of insulin was determined in 1969 by D.C. Hodgkin et al. following a 35-year program of research. This structure depicted a hexamer remarkable for its self-assembly as a zinc-coordinated trimer of dimer. Prominent at the dimer interface was an "aromatic triplet" of conserved residues at consecutive positions in the B chain: Phe(B24) , Phe(B25) and Tyr(B26) . The elegance of this interface inspired the Oxford team to poetry: "A thing of beauty is a joy forever" (John Keats as quoted by Blundell, T.L., et al. Advances in Protein Chemistry 26:279-286 [1972]). Here, we revisit this aromatic triplet in light of recent advances in the structural biology of insulin bound as a monomer to fragments of the insulin receptor. Such co-crystal structures have defined how these side chains pack at the primary hormone-binding surface of the receptor ectodomain. On receptor binding, the B-chain beta-strand (residues B24-B28) containing the aromatic triplet detaches from the alpha-helical core of the hormone. Whereas Tyr(B26) lies at the periphery of the receptor interface and may functionally be replaced by a diverse set of substitutions, Phe(B24) and Phe(B25) engage invariant elements of receptor domains L1 and alphaCT. These critical contacts were anticipated by the discovery of diabetes-associated mutations at these positions by Donald Steiner et al. at the University of Chicago. Conservation of Phe(B24) , Phe(B25) and Tyr(B26) among vertebrate insulins reflects the striking confluence of structure-based evolutionary constraints: foldability, protective self-assembly and hormonal activity.
Publisher
Wiley
Research Division(s)
Structural Biology
PubMed ID
30230175
NHMRC Grants
NHMRC/1058233
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-09-21 02:32:27
Last Modified: 2018-09-21 03:05:11
An error has occurred. This application may no longer respond until reloaded. Reload 🗙