HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ye, Q. Articles by Jia, Z. Search for Related Content PubMed PubMed Citation Articles by Ye, Q. Articles by Jia, Z. Social Bookmarking                   What's this?

High-resolution crystal structure of apolipoprotein(a) kringle IV type 7: Insights into ligand binding

Department of Biochemistry, Queen's University, Kingston, Ontario, Canada, K7L 3N6

Reprint requests to: Dr. Zongchao Jia, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6; e-mail: jia{at}post.queensu.ca; fax: 613-533-2497.

Apolipoprotein(a) [apo(a)] consists of a series of tandemly repeated modules known as kringles that are commonly found in many proteins involved in the fibrinolytic and coagulation cascades, such as plasminogen and thrombin, respectively. Specifically, apo(a) contains multiple tandem repeats of domains similar to plasminogen kringle IV (designated as KIV₁ to KIV₁₀) followed by sequences similar to the kringle V and protease domains of plasminogen. The KIV domains of apo(a) differ with respect to their ability to bind lysine or lysine analogs. KIV₁₀ represents the high-affinity lysine-binding site (LBS) of apo(a); a weak LBS is predicted in each of KIV₅–KIV₈ and has been directly demonstrated in KIV₇. The present study describes the first crystal structure of apo(a) KIV₇, refined to a resolution of 1.45 Å, representing the highest resolution for a kringle structure determined to date. A critical substitution of Tyr-62 in KIV₇ for the corresponding Phe-62 residue in KIV₁₀, in conjunction with the presence of Arg-35 in KIV₇, results in the formation of a unique network of hydrogen bonds and electrostatic interactions between key LBS residues (Arg-35, Tyr-62, Asp-54) and a peripheral tyrosine residue (Tyr-40). These interactions restrain the flexibility of key LBS residues (Arg-35, Asp-54) and, in turn, reduce their adaptability in accommodating lysine and its analogs. Steric hindrance involving Tyr-62, as well as the elimination of critical ligand-stabilizing interactions within the LBS are also consequences of this interaction network. Thus, these subtle yet critical structural features are responsible for the weak lysine-binding affinity exhibited by KIV₇ relative to that of KIV₁₀.

Keywords: Apolipoprotein(a); kringle; lysine binding; crystal structure

Abbreviations: Lp(a), lipoprotein(a) • LDL, low-density lipoprotein • apoB-100, apolipoprotein B-100 • apo(a), apolipoprotein(a) • Pgn, plasminogen • K, kringle • ECM, extracellular matrix • LBS, lysine-binding site(s) • Lys-, lysine-binding deficiency • K_d, dissociation constant

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. J. Sharp, M. A. Perugini, S. M. Marcovina, and S. P. A. McCormick Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly J. Lipid Res., December 1, 2004; 45(12): 2227 - 2234. [Abstract] [Full Text] [PDF]

				L. Becker, P. M. Cook, T. G. Wright, and M. L. Koschinsky Quantitative Evaluation of the Contribution of Weak Lysine-binding Sites Present within Apolipoprotein(a) Kringle IV Types 6-8 to Lipoprotein(a) Assembly J. Biol. Chem., January 23, 2004; 279(4): 2679 - 2688. [Abstract] [Full Text] [PDF]

				C. Y. Y. Liu, R. Broadhurst, S. M. Marcovina, and S. P. A. McCormick Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation J. Lipid Res., January 1, 2004; 45(1): 63 - 70. [Abstract] [Full Text] [PDF]

				R. J. Sharp, M. A. Perugini, S. M. Marcovina, and S. P.A. McCormick A Synthetic Peptide That Inhibits Lipoprotein(a) Assembly Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 502 - 507. [Abstract] [Full Text] [PDF]