PDBsum entry 1auq

Willebrand

PDB id: 1auq

Contents

Protein chain

208 a.a. *

Metals

_CD

Waters ×91

* Residue conservation analysis

PDB id:

1auq

Name:

Willebrand

Title:

A1 domain of von willebrand factor

Structure:

A1 domain of von willebrand factor. Chain: a. Fragment: a1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.186 R-free: 0.248

Authors:

J.Emsley,M.Cruz,R.Handin,R.Liddington

Key ref:

J.Emsley et al. (1998). Crystal structure of the von Willebrand Factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem, 273, 10396-10401. PubMed id: 9553097 DOI: 10.1074/jbc.273.17.10396

Date:

01-Sep-97 Release date: 14-Oct-98

Protein chain

P04275  (VWF_HUMAN) -  von Willebrand factor from Homo sapiens

Seq: 2813 a.a.

Struc: 208 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1074/jbc.273.17.10396

J Biol Chem 273:10396-10401 (1998)

PubMed id: 9553097

Crystal structure of the von Willebrand Factor A1 domain and implications for the binding of platelet glycoprotein Ib.

J.Emsley, M.Cruz, R.Handin, R.Liddington.

ABSTRACT

von Willebrand Factor (vWF) is a multimeric protein that mediates platelet adhesion to exposed subendothelium at sites of vascular injury under conditions of high flow/shear. The A1 domain of vWF (vWF-A1) forms the principal binding site for platelet glycoprotein Ib (GpIb), an interaction that is tightly regulated. We report here the crystal structure of the vWF-A1 domain at 2.3-A resolution. As expected, the overall fold is similar to that of the vWF-A3 and integrin I domains. However, the structure also contains N- and C-terminal arms that wrap across the lower surface of the domain. Unlike the integrin I domains, vWF-A1 does not contain a metal ion-dependent adhesion site motif. Analysis of the available mutagenesis data suggests that the activator botrocetin binds to the right-hand face of the domain containing helices alpha5 and alpha6. Possible binding sites for GpIb are the front and upper surfaces of the domain. Natural mutations that lead to constitutive GpIb binding (von Willebrand type IIb disease) cluster in a different site, at the interface between the lower surface and the terminal arms, suggesting that they disrupt a regulatory region rather than forming part of the primary GpIb binding site. A possible pathway for propagating structural changes from the regulatory region to the ligand-binding surface is discussed.

Selected figure(s)

Figure 2.
Fig. 2. Stereo C plot comparing vWF-A1 (solid lines) with vWF-A3 (dashed lines). The two molecules have been superimposed using MULTIFIT (25). The N and C termini of vWF-A1 are labeled. Every 10th residue (starting at 506) is shown as a small circle, with occasional numbering. The N- and C-proximal cysteines forming the disulfide bridge are shown as large circles.

Figure 3.
Fig. 3. Main chain schematic of the vWF-A1 domain, with -strands (arrows) and helices (coils) (drawn with MOLSCRIPT, RASTER3D, and RENDER (32-34)). The two cysteines involved the disulfide bridge are shown as yellow spheres. Sites of von Willebrand disease type IIb mutations (both natural and induced) are shown as red spheres. Mutants with reduced botrocetin binding are in green. Mutations with selective loss-of-function (reduced ristocetin-induced binding but normal botrocetin-induced binding) are in cyan (23) or black (26), and a mutant with reduced GpIb binding but normal botrocetin binding is in blue (23). The mutation of KKKK642-645 in the 5- E loop also reduces binding to heparin (26). For multiple site mutants, spheres are placed near the midpoint of the mutation.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (1998, 273, 10396-10401) copyright 1998.

Figures were selected by an automated process.