2feb
From Proteopedia
|
NMR Solution Structure, Dynamics and Binding Properties of the Kringle IV Type 8 module of apolipoprotein(a)
Overview
The plasma lipoprotein lipoprotein(a) [Lp(a)] comprises a low-density, lipoprotein (LDL)-like particle covalently attached to the glycoprotein, apolipoprotein(a) [apo(a)]. Apo(a) consists of multiple tandem repeating, kringle modules, similar to plasminogen kringle IV (designated, KIV1-KIV10), followed by modules homologous to the kringle V module and, protease domain of plasminogen. The apo(a) KIV modules have been, classified on the basis of their binding affinity for lysine and lysine, analogues. The strong lysine-binding apo(a) KIV10 module mediates, lysine-dependent interactions with fibrin and cell-surface receptors. Weak, lysine-binding apo(a) KIV7 and KIV8 modules display a 2-3-fold difference, in lysine affinity and play a direct role in the noncovalent step in Lp(a), assembly through binding to unique lysine-containing sequences in, apolipoproteinB-100 (apoB-100). The present study describes the nuclear, magnetic resonance solution structure of apo(a) KIV8 and its solution, dynamics properties, the first for an apo(a) kringle module, and compares, the effects of epsilon-aminocaproic acid (epsilon-ACA) binding on the, backbone and side-chain conformation of KIV7 and KIV8 on a per residue, basis. Apo(a) KIV8 adopts a well-ordered structure that shares the general, tri-loop kringle topology with apo(a) KIV6, KIV7, and KIV10. Mapping of, epsilon-ACA-induced chemical-shift changes on KIV7 and KIV8 indicate that, the same residues are affected, despite a 2-3-fold difference in, epsilon-ACA affinity. A unique loop conformation within KIV8, involving, hydrophobic interactions with Tyr40, affects the positioning of Arg35, relative to the lysine-binding site (LBS). A difference in the orientation, of the aromatic side chains comprising the hydrophobic center of the LBS, in KIV8 decreases the size of the hydrophobic cleft compared to other, apo(a) KIV modules. An exposed hydrophobic patch contiguous with the LBS, in KIV8 and not conserved in other weak lysine-binding apo(a) kringle, modules may modulate specificity for regions within apoB-100. An, additional ligand recognition site comprises a structured, arginine-glycine-aspartate motif at the N terminus of the KIV8 module, which may mediate Lp(a)/apo(a)-integrin interactions.
About this Structure
2FEB is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Nuclear magnetic resonance (NMR) solution structure, dynamics, and binding properties of the kringle IV type 8 module of apolipoprotein(a)., Chitayat S, Kanelis V, Koschinsky ML, Smith SP, Biochemistry. 2007 Feb 20;46(7):1732-42. Epub 2007 Jan 31. PMID:17263558
Page seeded by OCA on Wed Jan 23 13:55:29 2008
