Sequences of B-Chain/Domain 1−10/1−9 of Insulin and Insulin-like Growth Factor 1 Determine Their Different Folding Behavior

Chen, Yan; You, You; Jin, Rui; Guo, Zhan‐Yun; Yang, Feng

doi:10.1021/bi049710y

Cited by 14 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Containing respective pairings (A20‐B19, A7‐B7, A6‐A11) (native) and (A20‐B19, A6‐B7, A7‐A11) ( swap ), the isomers exhibit similar core structures near the shared A20‐B19 disulphide bridge . In a “mini‐IGF” model, the relative stabilities of these disulphide isomers is influenced by the N‐terminal segment of the B domain . In human proinsulin, an homologous non‐native isomer and yet another (with pairings [A20‐B19, A11‐B7, A6‐A7]) forms in the presence of a chemical denaturant .…”

Section: Proinsulin Structural Features That Are a Consequence Of Evomentioning

confidence: 99%

Biosynthesis, structure, and folding of the insulin precursor protein

Liu

Weiss

Arunagiri

et al. 2018

Diabetes Obesity Metabolism

160

165

View full text Add to dashboard Cite

Insulin synthesis in pancreatic β-cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and postprandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor includes elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation and signal peptide cleavage of preproinsulin-all of which are necessary to initiate the pathway of proper proinsulin folding. Evolutionary pressures on the primary structure of proinsulin itself have preserved the efficiency of folding ("foldability"), and remarkably, these evolutionary pressures are distinct from those protecting the ultimate biological activity of insulin. Proinsulin foldability is manifest in the ER, in which the local environment is designed to assist in the overall load of proinsulin folding and to favour its disulphide bond formation (while limiting misfolding), all of which is closely tuned to ER stress response pathways that have complex (beneficial, as well as potentially damaging) effects on pancreatic β-cells. Proinsulin misfolding may occur as a consequence of exuberant proinsulin biosynthetic load in the ER, proinsulin coding sequence mutations, or genetic predispositions that lead to an altered ER folding environment. Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene-induced Diabetes of Youth (MIDY), animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.

show abstract

Section: Proinsulin Structural Features That Are a Consequence Of Evomentioning

confidence: 99%

Biosynthesis, structure, and folding of the insulin precursor protein

Liu

Weiss

Arunagiri

et al. 2018

Diabetes Obesity Metabolism

160

165

View full text Add to dashboard Cite

show abstract

“…36) Moreover, the sequences of the B domain in IGF-I play an important role in guiding its unique bifurcating folding behavior. 37,38) Mature Amur tiger IGF-I was 100% identical to that of human and horse and was highly conserved in those of the other species. The B-and A-domains of Amur tiger IGF-I showed a high degree of sequence identity.…”

Section: Discussionmentioning

confidence: 94%

Cloning, Characterization and Tissue Specific Expression of Amur Tiger (Panthera tigris altaica) IGF-I

Zhu

Zhang

et al. 2006

Bioscience, Biotechnology, and Biochemistry

View full text Add to dashboard Cite

Insulin-like growth factor I (IGF-I) plays an important role in regulating gonad function, which is essential for normal reproduction in animals, especially in sexual receptivity and reproductive behavior. In this study, a cDNA encoding Amur tiger (Panthera tigris altaica) IGF-I was isolated from liver total RNA using RT-PCR. The IGF-I cDNA of Amur tiger (ATIGF-I) was highly homologous to that of other animals, 84.8% to rat, 93.7% to human and horse. Alignment analysis showed that the cysteine residues and many amino acid residues of putative mature ATIGF-I are highly conserved in mammalian species, confirming the high sequence homology observed in other species. DNA encoding the mature ATIGF-I peptide was ligated with pET-DsbA expression vector and highly expressed in Escherichia coli BL21 with IPTG induction. The recombinant proteins expressed existed mostly in the soluble protein fraction, and were purified with metal affinity resins. Western blotting confirmed that the recombinant proteins reacted with antibodies against IGF-I. The results obtained here should be useful for large-scale production of biological active ATIGF-I protein, as well as for further research on growth, development, and reproduction in the Amur tiger. Tissue specific expression of ATIGF-I mRNA in the Amur tiger was examined by reverse transcription-polymerase chain reaction (RT-PCR), The major ATIGF-I mRNA expression tissue was the liver, while medium signals were found in the uterus, ovary, and pituitary, and minor signals were detected in various tissues including the heart, spleen, pancreas, and kidney. The results indicate that IGF-I might play an important role in the reproductive system and in cub development in the Amur tiger.

show abstract

“…That the number of products is precisely two demonstrates that a non-random folding pathway is encoded but must be "ambiguous" following formation of cystine- (18 -61). Studies of chimeric PIP analogs indicate that the respective B-domains of proinsulin and IGF-I are responsible for determining the relative stability of the swapped isomer (72). Specification of native IGF-I disulfide pairing in vivo is attributed to specific IGF-1-binding proteins, present in equimolar proportions.…”

Section: Discussionmentioning

confidence: 99%

The Folding Nucleus of the Insulin Superfamily

Hua

Mayer

Jia

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

The vertebrate insulin-related superfamily consists of insulin, insulin-related growth factors (IGF-I and IGF-II), 2 (1, 2), relaxin (3-5), and relaxin-related factors (6 -9). Insulin and IGFs function as ligands for receptor tyrosine kinases (10, 11), whereas relaxin and related factors bind to G-protein coupled receptors (12). These proteins exhibit homologous ␣-helical domains and disulfide bridges (1-9). Canonical cystines (using an insulin-based nomenclature) are A6 -A11, A7-B7, and A20 -B19 (Fig. 1A); corresponding cystines in IGF-I span residues 47-52, 6 -48, and 18 -61 (Fig. 1B). Whereas insulin and relaxin contain two chains (designated A and B) as a consequence of post-translational processing (3-5, 13), IGFs are single-chain polypeptides containing A-and B-domains, an intervening connecting (C) domain, and C-terminal D-domain (1, 2). In this article we describe the design, synthesis, and conformational repertoire of a peptide model of a key IGF-I folding intermediate (14,15). Designated IGF-p, the disulfide-linked peptide contains about half of the IGF-I sequence (Fig. 2, A and B). Although not well ordered, IGF-p exhibits an unexpected richness of nascent structure. Its conformational propensities, foreshadowing the structure of the native state, suggest a model for an IGF-I folding nucleus. This model is likely to generalize to other members of the insulin-related superfamily, including proinsulin.Our studies are motivated by general principles of protein folding and their application to the insulin-related superfamily. The native state of a globular protein may be viewed as the coalescence of discrete subdomains (16). Folding trajectories exhibit transient formation and stabilization of native-like elements of secondary structure (17). 3 Coalescence of resulting microdomains is consistent with classical diffusion-collision and framework mechanisms (18). Although the existence of funnel-like free-energy landscapes suggest the importance of parallel events in folding (19), preferred trajectories may exist (20), effectively defining predominant classes of structural intermediates. Associated transition states and intermediates have been probed by respective analyses of residue-specific values (21) and hydrogen-deuterium exchange (22). Structural insights have been obtained from equilibrium models of proteinfolding intermediates (23, 24), including peptide fragments (25,26).Studies of the disulfide-coupled refolding of small globular proteins have exploited chemical trapping of preferred kinetic intermediates (27). Refolding of IGF-I and a singlechain proinsulin analog (mini-proinsulin, also designated porcine insulin precursor (PIP) (28)) is notable for populated one-and two-disulfide intermediates (14,29,30). A key role * This work was supported in part by National Institutes of Health Grant DK0697674 (to M. A. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Se...

show abstract

Sequences of B-Chain/Domain 1−10/1−9 of Insulin and Insulin-like Growth Factor 1 Determine Their Different Folding Behavior

Cited by 14 publications

References 32 publications

Biosynthesis, structure, and folding of the insulin precursor protein

Biosynthesis, structure, and folding of the insulin precursor protein

Cloning, Characterization and Tissue Specific Expression of Amur Tiger (Panthera tigris altaica) IGF-I

The Folding Nucleus of the Insulin Superfamily

Contact Info

Product

Resources

About