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

Citation
Ql. Ye et al., High-resolution crystal structure of apolipoprotein(a) kringle IV type 7: Insights into ligand binding, PROTEIN SCI, 10(6), 2001, pp. 1124-1129
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
PROTEIN SCIENCE
ISSN journal
0961-8368 → ACNP
Volume
10
Issue
6
Year of publication
2001
Pages
1124 - 1129
Database
ISI
SICI code
0961-8368(200106)10:6<1124:HCSOAK>2.0.ZU;2-F
Abstract
Apolipoprotein(a) [apo(a)] consists of a series of tandemly repeated module s known as kringles that are commonly found in many proteins involved in th e fibrinolytic and coagulation cascades, such as plasminogen and thrombin, respectively. Specifically, apo(a) contains multiple tandem repeats of doma ins similar to plasminogen kringle IV (designated as KIV1 to KIV10) followe d 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 ly sine or lysine analogs. KIV10 represents the high-affinity lysine-binding s ite (LBS) of apo(a); a weak LBS is predicted in each of KIV5-KIV8 and has b een directly demonstrated in KIV7. The present study describes the first cr ystal structure of apo(a) KIV7, refined to a resolution of 1.45 Angstrom, r epresenting the highest resolution for a kringle structure determined to da te. 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, resul ts 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 perip heral tyrosine residue (Tyr-40). These interactions restrain the flexibilit y of key LBS residues (Arg-35, Asp-54) and, in turn, reduce their adaptabil ity 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, th ese subtle yet critical structural features are responsible for the weak ly sine-binding affinity exhibited by KIV7 relative to that of KIV10.