Collagen, one of the most abundant proteins of the extracellular matrix, provides structural integrity in the human body and is responsible for multiple interactions with cells and other matrix molecules. Many common diseases, such as arthritis, diabetes, and cancer involve abnormal regulation or reactivity of collagen and certain collagen genetic diseases result in connective tissue disease or aortic aneurism. The objective of this proposal is to develop a mechanistic understanding of the interactions of the collagen ligand with its receptors and to understand the molecular basis of Osteogenesis Imperfecta (OI), a genetic disease that results in brittle bones. We propose to use an integrated approach based on NMR in conjunction with computational, biophysical methods, and in vitro functional assays to provide unique structural and dynamic insight these questions.
The specific aims of the proposal include 1) characterizing the structure and dynamics of the interactions between the integrin I domain and collagen;2) defining the sequence dependence and molecular mechanism of Gly mutations leading to collagen diseases: prediction of OI phenotype and 3) characterizing interactions of matrix metalloproteinases (MMPs) and integrin I-domain receptors with triple helical motifs that contain imperfect (GXY)n sequences at, or near, the binding regions. In order to achieve these aims we will develop some novel methodology designed to 1) achieve better structural and dynamic characterization of the collagen model peptides;these are long anisotropic molecules that are difficult to characterize by standard protocols and integration of NMR and MD simulations will provide a new approach for investigation of these unusual systems. 2) Using statistical approaches, develop consensus sequence patterns that define lethal and nonlethal phenotypes in OI;these will be used to begin to establish predictions of phenotype based on sequence and conformational fluctuations. The biomedical importance of collagen has led to increasing interest in the structural and biological role of this protein makin the collagen triple helix an extremely important target for probing sequence-structure-function relationships and for understanding the molecular basis of collagen/receptor biological interactions. Characterizing the collagen triple helix conformation and dynamics alone, and in combination with its binding partners, will help understand its role in disease and ligand recognition, and aid in drug discovery programs.

Public Health Relevance

The tremendous biomedical importance of collagen makes the collagen triple helix an important target for establishing sequence-structure-function relationships to understand its structural and biological role. We will develop an integrated approach based on NMR in conjunction with computational, biophysical methods, and in vitro functional assays to provide insight into the recognition mechanism of the collagen triple helix with integrin and to understand the molecular basis of genetic collagen diseases arising from mutations. These studies will provide new insight into drug therapy approaches that target the unique triple helix motif.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function C Study Section (MSFC)
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Wehrle, Janna P
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Kim, Seho; Wu, Kuen-Phon; Baum, Jean (2013) Fast hydrogen exchange affects ýýýýýN relaxation measurements in intrinsically disordered proteins. J Biomol NMR 55:249-56
Kang, Lijuan; Wu, Kuen-Phon; Vendruscolo, Michele et al. (2011) The A53T mutation is key in defining the differences in the aggregation kinetics of human and mouse ?-synuclein. J Am Chem Soc 133:13465-70
Wu, Kuen-Phon; Weinstock, Daniel S; Narayanan, Chitra et al. (2009) Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations. J Mol Biol 391:784-96
Chen, Yu-Jen; Wu, Kuen-Phon; Kim, Seho et al. (2008) Backbone NMR assignments of DFP-inhibited mature subtilisin E. Biomol NMR Assign 2:131-3
Brodsky, Barbara; Baum, Jean (2008) Structural biology: Modelling collagen diseases. Nature 453:998-9
Madhan, Balaraman; Xiao, Jianxi; Thiagarajan, Geetha et al. (2008) NMR monitoring of chain-specific stability in heterotrimeric collagen peptides. J Am Chem Soc 130:13520-1
Wei, Yinan; Kim, Seho; Fela, David et al. (2003) Solution structure of a de novo protein from a designed combinatorial library. Proc Natl Acad Sci U S A 100:13270-3
Wei, Yinan; Fela, David; Kim, Seho et al. (2003) 1H, 13C and 15N resonance assignments of S-824, a de novo four-helix bundle from a designed combinatorial library. J Biomol NMR 27:395-6