A peptide approach to a comprehensive understanding of the effect of amino acid sequence (Gly-X-Y)n on the stability, conformation, folding, dynamics and self-association of the normal and mutant collagen triple-helix is in progress. Our goals are to complete sequence-stability correlations at the molecular level; to develop peptides to model triple-helix self-association; and to pursue the disruption caused by Gly substitutions found in collagen diseases. Previous host-guest peptide studies established the triple-helix propensities of all 20 amino acids for the X and Y positions, and evaluation of molecular interactions within the triple-helix will be completed. These relationships between Gly-X-Y sequence and stability will be used to formulate predictions for the global stability of collagen model peptides and to relate local stability variations along collagen with ligand binding sites, microunfolding implicated in fibril formation, and the clinical severity of mutations. Calorimetric investigations are proposed to elaborate the mechanism of hydroxyproline stabilization of the triple-helix, and studies are proposed to further investigate the recently established sequence related modulation of triple-helix twist. An important goal is to establish a peptide system to model the self-association of triple-helices, since collagens function in supramolecular assemblies and some collagen mutations are pathological because of their influence on higher order structure. Strategies to design self-associating peptides will include pairs of oppositely charged residues to promote in register arrays and adaptation of sticky end and repeating pattern designs to form staggered arrays. Studies are proposed on peptide models of type I collagen mutations leading to a bone disease (osteogenesis imperfecta) and of type VII collagen mutations leading to a blistering skin disease (dystrophoic form of epidermolysis bullosa). The effect of the immediate sequence environment of the mutation and the identity of the residue replacing the Gly will be examined. Placing collagen structure, dynamics, and folding in a solid physicochemical framework through peptide studies will provide a context for understanding normal biological activities of selfassociation and binding, and for the changes occurring in many diseases affected by this abundant protein.
| Qiu, Yimin; Poppleton, Erik; Mekkat, Arya et al. (2018) Enzymatic Phosphorylation of Ser in a Type I Collagen Peptide. Biophys J 115:2327-2335 |
| Qiu, Yimin; Mekkat, Arya; Yu, Hongtao et al. (2018) Collagen Gly missense mutations: Effect of residue identity on collagen structure and integrin binding. J Struct Biol 203:255-262 |
| Mekkat, Arya; Poppleton, Erik; An, Bo et al. (2018) Effects of flexibility of the ?2 chain of type I collagen on collagenase cleavage. J Struct Biol 203:247-254 |
| Marcink, Tara C; Simoncic, Jayce A; An, Bo et al. (2018) MT1-MMP Binds Membranes by Opposite Tips of Its ? Propeller to Position It for Pericellular Proteolysis. Structure : |
| Brodsky, Barbara; Ramshaw, John A M (2017) Bioengineered Collagens. Subcell Biochem 82:601-629 |
| Walker, Kenneth T; Nan, Ruodan; Wright, David W et al. (2017) Non-linearity of the collagen triple helix in solution and implications for collagen function. Biochem J 474:2203-2217 |
| An, Bo; Brodsky, Barbara (2016) Collagen binding to OSCAR: the odd couple. Blood 127:521-2 |
| Yigit, Sezin; Yu, Hongtao; An, Bo et al. (2016) Mapping the Effect of Gly Mutations in Collagen on ?2?1 Integrin Binding. J Biol Chem 291:19196-207 |
| An, Bo; Lin, Yu-Shan; Brodsky, Barbara (2016) Collagen interactions: Drug design and delivery. Adv Drug Deliv Rev 97:69-84 |
| An, Bo; Abbonante, Vittorio; Xu, Huifang et al. (2016) Recombinant Collagen Engineered to Bind to Discoidin Domain Receptor Functions as a Receptor Inhibitor. J Biol Chem 291:4343-55 |
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