PDBsum entry 2h41

Cell adhesion, structural protein

PDB id: 2h41

Contents

Protein chain

95 a.a. *

* Residue conservation analysis

PDB id:

2h41

Name:

Cell adhesion, structural protein

Title:

Solution structure of the second type iii domain of human fibronectin: minimized average structure

Structure:

Fibronectin. Chain: a. Fragment: fibronectin type-iii 2(2f3). Synonym: fn, cold-insoluble globulin, cig. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fn1. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

1 models

Authors:

I.Vakonakis,I.D.Campbell

Key ref:

I.Vakonakis et al. (2007). Interdomain association in fibronectin: insight into cryptic sites and fibrillogenesis. EMBO J, 26, 2575-2583. PubMed id: 17464288 DOI: 10.1038/sj.emboj.7601694

Date:

23-May-06 Release date: 10-Apr-07

Protein chain

P02751  (FINC_HUMAN) -  Fibronectin from Homo sapiens

Seq: 2477 a.a.

Struc: 95 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1038/sj.emboj.7601694

EMBO J 26:2575-2583 (2007)

PubMed id: 17464288

Interdomain association in fibronectin: insight into cryptic sites and fibrillogenesis.

I.Vakonakis, D.Staunton, L.M.Rooney, I.D.Campbell.

ABSTRACT

The process by which fibronectin (FN), a soluble multidomain protein found in tissue fluids, forms insoluble fibrillar networks in the extracellular matrix is poorly understood. Cryptic sites found in FN type III domains have been hypothesized to function as nucleation points, thereby initiating fibrillogenesis. Exposure of these sites could occur upon tension-mediated mechanical rearrangement of type III domains. Here, we present the solution structures of the second type III domain of human FN ((2)FNIII), and that of an interaction complex between the first two type III domains ((1-2)FNIII). The two domains are connected through a long linker, flexible in solution. A weak but specific interdomain interaction maintains (1-2)FNIII in a closed conformation that associates weakly with the FN N-terminal 30 kDa fragment (FN30 kDa). Disruption of the interdomain interaction by amino-acid substitutions dramatically enhances association with FN30 kDa. Truncation analysis of (1-2)FNIII reveals that the interdomain linker is necessary for robust (1-2)FNIII-FN30 kDa interaction. We speculate on the importance of this interaction for FN function and present a possible mechanism by which tension could initiate fibrillogenesis.

Selected figure(s)

Figure 3.
Figure 3 (A, B) Representative structures of the two different ^1-2FNIII forms present in the structure calculation. Occupancy of form A in the final ensemble was 78%, whereas that of form B was 22%. Side chains for two residues, K669 and D767, involved in an electrostatic interaction in form A but not form B, are shown. D767 is also involved in electrostatic interactions with K672 in population A, and participates in an extended hydrogen bond and electrostatics network on the ^1FNIII binding interface of ^2FNIII. The interdomain linker is schematically represented as a dashed line. (C, D) ^1-2FNIII structure. Shown here are: the final 39-structure ensemble of ^1-2FNIII structures displaying (C) or omitting (D) the flexible ^1FNIII–^2FNIII linker. Secondary structure elements are colored cyan and purple for ^1FNIII and ^2FNIII, respectively.

Figure 5.
Figure 5 Possible fibrillogenesis mechanism: FN molecules exist in solution, with the ^1-2FNIII domain pair in closed conformation, likely interacting with the FN N-terminus as part of a larger globular structure (A). Under tension, the FN globular structure and the ^1FNIII–^2FNIII interaction are disrupted (B, C). This allows the ^1-2FNIII open conformation to strongly associate with the N-terminus of other FN molecules (C) and, along with the disulfide crosslinks at the FN C-terminus, create FN fibrils. The different domain types of FN are shown in gold (FNI), purple (FNII) or cyan (FNIII). The different FN fragments shown correspond to: FN30 kDa, ^1-5FNI; gelatin binding domain, ^6FNI-^1-2FNII-^7-9FNI.

The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2007, 26, 2575-2583) copyright 2007.

Figures were selected by the author.