Barbara Brodsky Professor UMDNJ Dept. Biochemistry - Room 609 Piscataway. NJ 08854 (732) 235-4048 FAX - 4783 brodsky@umdnj.edu

Structural studies of peptide models of normal collagen and its mutations in diseases

The aims of our laboratory are to use triple-helical peptides of defined sequence to determine how amino acid sequence affects triple-helix structure and recognition. and how alterations in the triple-helix can lead to molecular defects in collagen diseases. Triple-helical domains are important both as a rod-like structural component and for interactions with other molecules in collagens and in a range of host-defense proteins. Synthetic triple-helical peptides have been designed to model biologically important regions of collagen and of the macrophage scavenger receptor. The conformation. stability. dynamics. folding and binding of these peptides are being characterized through the use of circular dichroism spectroscopy. calorimetry. NMR spectroscopy. molecular modeling. and x-ray crystallography. Mutations that interrupt the repeating (Gly-X-Y)n have been found to lead to connective tissue diseases. and studies are being done to investigate the structural basis of these pathological changes. Recent accomplishments include determination of the first crystal structures of a triple-helix. in collaboration with the laboratory of Dr. Helen Berman; the first 2-D NMR structural and dynamics studies on a triple-helix. in collaboration with Dr. Jean Baum; establishment of propensities scales for the collagen triple-helix; and determining the degree of destabilization caused by different Gly mutations in collagen diseases.

Selected Publications

Kar K, Ibrar S, Nanda V, Getz TM, Kunapuli SP, Brodsky B. (2009) Aromatic interactions promote self-association of collagen triple-helical peptides to higher-order structures.
Biochemistry. 48(33):7959-68.

Yoshizumi A, Yu Z, Silva T, Thiagarajan G, Ramshaw JA, Inouye M, Brodsky B. (2009) Self-association of streptococcus pyogenes collagen-like constructs into higher order structures. Protein Sci. 18(6):1241-51.

Li Y, Brodsky B, Baum J. (2009) NMR conformational and dynamic consequences of a GLY to ser substitution in an osteogenesis imperfecta collagen model peptide. J Biol Chem. 284(31):20660-7.

Madhan B, Xiao J, Thiagarajan G, Baum J, Brodsky B. (2008) NMR monitoring of chain-specific stability in heterotrimeric collagen peptides. J Am Chem Soc. 130(41):13520-1.

Brodsky B, Baum J. (2008) Structural biology: Modelling collagen diseases. Nature. 453(7198):998-9.

Leo JC, Elovaara H, Brodsky B, Skurnik M, Goldman A. (2008) The Yersinia adhesin YadA binds to a collagenous triple-helical conformation but without sequence specificity. Protein Eng Des Sel. 21(8):475-84.

Kar K, Wang YH, Brodsky B. (2008) Sequence dependence of kinetics and morphology of collagen model peptide self-assembly into higher order structures. Protein Sci. 17(6):1086-95.

Bodian DL, Madhan B, Brodsky B, Klein TE. (2008) Predicting the clinical lethality of osteogenesis imperfecta from collagen glycine mutations. Biochemistry. 47(19):5424-32.

Gierasch LM, Deber CM, Brodsky B. (2008) Celebrating the scientific legacy of Elkan R. Blout. Biopolymers. 89(5):323.

Brodsky B, Thiagarajan G, Madhan B, Kar K. (2008) Triple-helical peptides: an approach to collagen conformation, stability, and self-association. Biopolymers. 89(5):345-53.

Thiagarajan G, Li Y, Mohs A, Strafaci C, Popiel M, Baum J, Brodsky B. (2008) Common interruptions in the repeating tripeptide sequence of non-fibrillar collagens: sequence analysis and structural studies on triple-helix peptide models. J Mol Biol. 376(3):736-48.

Mohs A, Silva T, Yoshida T, Amin R, Lukomski S, Inouye M, Brodsky B. (2007) Mechanism of stabilization of a bacterial collagen triple helix in the absence of hydroxyproline.
J Biol Chem. 282(41):29757-65.

Li Y, Brodsky B, Baum J. (2007) NMR shows hydrophobic interactions replace glycine packing in the triple helix at a natural break in the (Gly-X-Y)n repeat.
J Biol Chem. 282(31):22699-706.

Bryan MA, Brauner JW, Anderle G, Flach CR, Brodsky B, Mendelsohn R. (2007) FTIR studies of collagen model peptides: complementary experimental and simulation approaches to conformation and unfolding. J Am Chem Soc. 129(25):7877-84.

Mohs A, Popiel M, Li Y, Baum J, Brodsky B. (2006) Conformational features of a natural break in the type IV collagen Gly-X-Y repeat. J Biol Chem. 281(25):17197-202.

Hyde TJ, Bryan MA, Brodsky B, Baum J. (2006) Sequence dependence of renucleation after a Gly mutation in model collagen peptides. J Biol Chem. 281(48):36937-43.

Kar K, Amin P, Bryan MA, Persikov AV, Mohs A, Wang YH, Brodsky B. (2006) Self-association of collagen triple helic peptides into higher order structures. J Biol Chem. 281(44):33283-90.

Bella J, Liu J, Kramer R, Brodsky B, Berman HM. (2006) Conformational effects of Gly-X-Gly interruptions in the collagen triple helix. J Mol Biol. 362(2):298-311.

Silva T. Kirkpatrick A. Brodsky B. Ramshaw JA. (2005) Effect of deamidation on stability for the collagen to gelatin transition. J Agric Food Chem. 53(20):7802-6.

Li Y. Kim S. Brodsky B. Baum J. (2005) Identification of partially disordered peptide intermediates through residue-specific NMR diffusion measurements. J Am Chem Soc. 127(30):10490-1.

Brodsky B. Persikov AV. (2005) Molecular structure of the collagen triple helix. Adv Protein Chem. 70:301-39.

Persikov AV. Ramshaw JA. Brodsky B. (2005) Prediction of collagen stability from amino acid sequence. J Biol Chem. 280(19):19343-9.

Mohs A. Li Y. Doss-Pepe E. Baum J. Brodsky B. (2005) Stability junction at a common mutation site in the collagenous domain of the mannose binding lectin. Biochemistry. 44(6):1793-9.

Persikov AV. Ramshaw JA. Kirkpatrick A. Brodsky B. (2005) Electrostatic interactions involving lysine make major contributions to collagen triple-helix stability. Biochemistry. 44(5):1414-22.

Persikov AV. Pillitteri RJ. Amin P. Schwarze U. Byers PH. Brodsky B. (2004) Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum Mutat. 24(4):330-7.

Buevich AV. Silva T. Brodsky B. Baum J. (2004) Transformation of the mechanism of triple-helix peptide folding in the absence of a C-terminal nucleation domain and its implications for mutations in collagen disorders. J Biol Chem. 279(45):46890-5.

Doss-Pepe E. Deprez P. Silva T. Inestrosa NC. Kirkpatrick A. Ramshaw JA. Brodsky B. (2004) Stepwise construction of triple-helical heparin binding sites using peptide models. Biochim Biophys Acta. 1698(2):187-95.

Persikov AV. Xu Y. Brodsky B. (2004) Equilibrium thermal transitions of collagen model peptides. Protein Sci. Apr;13(4):893-902.

Persikov. A.V.. Ramshaw. J.A.. Kirkpatrick. A.. and Brodsky. B. (2003) Triple-helix propensity of hydroxyproline and fluoroproline: comparison of host-guest and repeating tripeptide collagen models. J. Am. Chem. Soc. 125:11500-1.