Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin.

Nanjo, Kishio; Sanke, Tokio; Miyano, Motoshige; Okai, Kazuhiko; Sowa, Ryoichi; Kondo, Mizuho; Nishimura, Susumu; Iwo, Kazuhiro; Miyamura, Kei; Given, Bruce D.

doi:10.1172/jci112331

Cited by 96 publications

(65 citation statements)

References 35 publications

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“…The present structure rationalizes the reduced affinity of clinical variant Leu B25 -insulin Chicago (7) and essential inactivity of Leu A3 -insulin Wakayama (7,40). Receptor engagement at these sites reflects mutual induced fit.…”

Section: Discussionmentioning

confidence: 56%

Protective hinge in insulin opens to enable its receptor engagement

Menting

Yang

Chan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

147

257

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Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal Bchain segment, critical for protective self-assembly in β cells and receptor binding at target tissues. Insight may be obtained from truncated "microreceptors" that reconstitute the primary hormone-binding site (α-subunit domains L1 and αCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 β-turn, coupling reorientation of Phe B24 to a 60°rotation of the B25-B28 β-strand away from the hormone core to lie antiparallel to the receptor's L1-β 2 sheet. Opening of this hinge enables conserved nonpolar side chains (Ile A2 , Val A3 , Val B12 , Phe B24 , and Phe B25 ) to engage the receptor. Restraining the hinge by nonstandard mutagenesis preserves native folding but blocks receptor binding, whereas its engineered opening maintains activity at the price of protein instability and nonnative aggregation. Our findings rationalize properties of clinical mutations in the insulin family and provide a previously unidentified foundation for designing therapeutic analogs. We envisage that a switch between free and receptorbound conformations of insulin evolved as a solution to conflicting structural determinants of biosynthesis and function.diabetes mellitus | signal transduction | receptor tyrosine kinase | metabolism | protein structure H ow insulin engages the insulin receptor has inspired speculation ever since the structure of the free hormone was determined by Hodgkin and colleagues in 1969 (1, 2). Over the ensuing decades, anomalies encountered in studies of analogs have suggested that the hormone undergoes a conformational change on receptor binding: in particular, that the C-terminal β-strand of the B chain (residues B24-B30) releases from the helical core to expose otherwise-buried nonpolar surfaces (the detachment model) (3-6). Interest in the B-chain β-strand was further motivated by the discovery of clinical mutations within it associated with diabetes mellitus (DM) (7). Analysis of residuespecific photo-cross-linking provided evidence that both the detached strand and underlying nonpolar surfaces engage the receptor (8).The relevant structural biology is as follows. The insulin receptor is a disulfide-linked (αβ) 2 receptor tyrosine kinase (Fig. 1A), the extracellular α-subunits together binding a single insulin molecule with high affinity (9). Involvement of the two α-subunits is asymmetric: the primary insulin-binding site (site 1*) comprises the central β-sheet (L1-β 2 ) of the first leucine-rich repeat domain (L1) of one α-subunit and the partially helical Cterminal segment (αCT) of the other α-subunit (Fig. 1A) (10). Such binding initiates conformational changes leading to transphosphorylation of the β-subunits' intracellular tyrosine kinase (TK) domains. Structures of wild-type (WT) insulin (or analogs) bound to extracellular receptor fragments were recently...

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Section: Discussionmentioning

confidence: 56%

Protective hinge in insulin opens to enable its receptor engagement

Menting

Yang

Chan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

147

257

View full text Add to dashboard Cite

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“…Mutation C A6 Y was also detected in a Danish patient (diabetes onset, age 3 mo); however, DNA samples from 2 children of the proband, who presented with diabetes at 6.5 and 2.5 mo postpartum, were not available for analysis. All mutations found in patients with PNDM or infancy-onset diabetes were different from those previously described to lead to familial hyperinsulinemia or hyperproinsulinemia (19)(20)(21)(26)(27)(28)(29)(30)(31)(32). Notably, all affected residues -including C A6 (and C A11 ), L B6 , L B11 , and dibasic amino acids RR and KR, at the junctions between B-chain and C-peptide and between C-peptide and A-chain, respectively -are conserved among human, cow, pig, dog, rat, and mouse insulin I and II; between frog insulin I and II; and between eel and hagfish (33) (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/ JCI33777DS1).…”

Section: Mutational Analysismentioning

confidence: 82%

“…Previously, abnormal circulating proinsulin had been reported in subjects with elevated plasma levels of immunoreactive insulin but normal insulin sensitivity (19,21,27,28,30). Such patients with familial hyperproinsulinemia are diagnosed as adults with mild diabetes, impaired glucose tolerance (19-21, 27, 28, 30, 32), or even episodic hypoglycemia (26,31 (29).…”

Section: Discussionmentioning

confidence: 99%

Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

et al. 2008

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Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth.Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.

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“…In particular, the naturally occurring IGF-I mutation V44M found in a Dutch dwarf patient has a significant reduction in IGF-IR binding affinity compared with IGF-I (43,44). This position is equivalent to Val A3 in insulin, which is believed to be part of the classical binding surface and which is mutated in insulin Wakayama (45,46). In addition, several residues appear to be unique for IGF-I binding, such as Ala 8 (48).…”

Section: A17mentioning

confidence: 99%

Structural Basis for the Lower Affinity of the Insulin-like Growth Factors for the Insulin Receptor

Gauguin¹,

Klaproth²,

Sajid³

et al. 2008

Journal of Biological Chemistry

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Insulin and the insulin-like growth factors (IGFs) bind with high affinity to their cognate receptor and with lower affinity to the noncognate receptor. The major structural difference between insulin and the IGFs is that the IGFs are single chain polypeptides containing A-, B-, C-, and D-domains, whereas the insulin molecule contains separate A-and B-chains. The C-domain of IGF-I is critical for high affinity binding to the insulin-like growth factor I receptor, and lack of a C-domain largely explains the low affinity of insulin for the insulin-like growth factor I receptor. It is less clear why the IGFs have lower affinity for the insulin receptor. In this study, 24 insulin analogues and four IGF analogues were expressed and analyzed to explore the role of amino acid differences in the Aand B-domains between insulin and the IGFs in binding affinity for the insulin receptor. showed affinities similar to that of insulin for the insulin receptor. The mitogenic potency of these analogues correlated well with the binding properties. Thus, a small number of A-and B-domain substitutions that map to the IGF surface equivalent to the classical binding surface of insulin weaken two hotspots that bind to the insulin receptor site 1.

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Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin.

Abstract: We have identified a non-insulin-dependent diabetic patient with fasting hyperinsulinemia (90 ,uU/ml), an elevated insulin:C-peptide molar ratio (1.68; normal, 0.05-0.20

Cited by 96 publications

References 35 publications

Protective hinge in insulin opens to enable its receptor engagement

Protective hinge in insulin opens to enable its receptor engagement

Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

Structural Basis for the Lower Affinity of the Insulin-like Growth Factors for the Insulin Receptor

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