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Folding of pig gastric mucin non-glycosylated domains: a discrete molecular dynamics study.

ABSTRACT: Mucin glycoproteins consist of tandem-repeating glycosylated regions flanked by non-repetitive protein domains with little glycosylation. These non-repetitive domains are involved in polymerization of mucin and play an important role in the pH-dependent gelation of gastric mucin, which is essential for protecting the stomach from autodigestion. We examine folding of the non-repetitive sequence of PGM-2X (242 amino acids) and the von Willebrand factor vWF-C1 domain (67 amino acids) at neutral and low pH using discrete molecular dynamics (DMD) in an implicit solvent combined with a four-bead peptide model. Using the same implicit solvent parameters, folding of both domains is simulated at neutral and low pH. In contrast to vWF-C1, PGM-2X folding is strongly affected by pH as indicated by changes in the contact order, radius of gyration, free-energy landscape, and the secondary structure. Whereas the free-energy landscape of vWF-C1 shows a single minimum at both neutral and low pH, the free-energy landscape of PGM-2X is characterized by multiple minima that are more numerous and shallower at low pH. Detailed structural analysis shows that PGM-2X partially unfolds at low pH. This partial unfolding is facilitated by the C-terminal region GLU236-PRO242, which loses contact with the rest of the domain due to effective "mean-field" repulsion among highly positively charged N- and C-terminal regions. Consequently, at low pH, hydrophobic amino acids are more exposed to the solvent. In vWF-C1, low pH induces some structural changes, including an increased exposure of CYS at position 67, but these changes are small compared to those found in PGM-2X. For PGM-2X, the DMD-derived average ?-strand propensity increases from 0.26 ± 0.01 at neutral pH to 0.38 ± 0.01 at low pH. For vWF-C1, the DMD-derived average ?-strand propensity is 0.32 ± 0.02 at neutral pH and 0.35 ± 0.02 at low pH. The DMD-derived structural information provides insight into pH-induced changes in the folding of two distinct mucin domains and suggests plausible mechanisms of the aggregation/gelation of mucin.

SUBMITTER: Barz B

PROVIDER: S-EPMC3473135 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Folding of pig gastric mucin non-glycosylated domains: a discrete molecular dynamics study.

Barz Bogdan B Turner Bradley S BS Bansil Rama R Urbanc Brigita B

Journal of biological physics 20120928 4

Mucin glycoproteins consist of tandem-repeating glycosylated regions flanked by non-repetitive protein domains with little glycosylation. These non-repetitive domains are involved in polymerization of mucin and play an important role in the pH-dependent gelation of gastric mucin, which is essential for protecting the stomach from autodigestion. We examine folding of the non-repetitive sequence of PGM-2X (242 amino acids) and the von Willebrand factor vWF-C1 domain (67 amino acids) at neutral and ...[more]

PMID: 24615227

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Project description:The amyloid aggregation of human islet amyloid polypeptide (hIAPP) is associated with pancreatic β-cell death in type 2 diabetes. The S20G substitution of hIAPP (hIAPP(S20G)), found in Japanese and Chinese people, is more amyloidogenic and cytotoxic than wild-type hIAPP. Rat amylin (rIAPP) does not have aggregation propensity or cytotoxicity. Mounting evidence suggests that soluble low-molecular-weight amyloid oligomers formed during early aggregation are more cytotoxic than mature fibrils. The self-assembly dynamics and oligomeric conformations remain unknown because the oligomers are heterogeneous and transient. The molecular mechanism of sequence-variation rendering dramatically different aggregation propensity and cytotoxicity is also elusive. Here, we investigate the oligomerization dynamics and conformations of amyloidogenic hIAPP, hIAPP(S20G), and non-amyloidogenic rIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our simulation results demonstrated that all three monomeric amylin peptides mainly adopted an unstructured formation with partial dynamical helices near the N-terminus. Relatively transient β-hairpins were more abundant in hIAPP and hIAPP(S20G) than in rIAPP. The S20G-substituting mutant of hIAPP altered the turn region of the β-hairpin motif, resulting in more hydrophobic residue-pairwise contacts within the β-hairpin. Oligomerization dynamic investigation revealed that all three peptides spontaneously accumulated into helix-populated oligomers. The conformational conversion to form β-sheet-rich oligomers was only observed in hIAPP and hIAPP(S20G). The population of high-β-sheet-content oligomers was enhanced by S20G substitution. Interestingly, both hIAPP and hIAPP(S20G) could form β-barrel formations, and the β-barrel propensity of hIAPP(S20G) was three times larger than that of hIAPP. No β-sheet-rich or β-barrel formations were observed in rIAPP. Our direct observation of the correlation between β-barrel oligomer formation and cytotoxicity suggests that β-barrels might play a critically important role in the cytotoxicity of amyloidosis.

Dataset Information

Folding of pig gastric mucin non-glycosylated domains: a discrete molecular dynamics study.

Publications

Folding of pig gastric mucin non-glycosylated domains: a discrete molecular dynamics study.

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