PDBsum entry 3fje

Hormone

PDB id: 3fje

Contents

Protein chains

141 a.a. *

Ligands

SO4

FMT ×4

Waters ×159

* Residue conservation analysis

PDB id:

3fje

Name:

Hormone

Title:

Crystal structure of c83s mutant of human acidic fibroblast growth factor

Structure:

Heparin-binding growth factor 1. Chain: a, b. Synonym: hbgf-1, acidic fibroblast growth factor, afgf, beta- endothelial cell growth factor, ecgf-beta. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgf1, fgfa. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.10Å R-factor: 0.198 R-free: 0.235

Authors:

M.Blaber,J.Lee

Key ref:

J.Lee and M.Blaber (2009). Structural basis of conserved cysteine in the fibroblast growth factor family: evidence for a vestigial half-cystine. J Mol Biol, 393, 128-139. PubMed id: 19683004 DOI: 10.1016/j.jmb.2009.08.007

Date:

14-Dec-08 Release date: 06-Oct-09

Protein chains

P05230  (FGF1_HUMAN) -  Fibroblast growth factor 1 from Homo sapiens

Seq: 155 a.a.

Struc: 141 a.a.*

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

DOI no: 10.1016/j.jmb.2009.08.007

J Mol Biol 393:128-139 (2009)

PubMed id: 19683004

Structural basis of conserved cysteine in the fibroblast growth factor family: evidence for a vestigial half-cystine.

J.Lee, M.Blaber.

ABSTRACT

The 22 members of the mouse/human fibroblast growth factor (FGF) family of proteins contain a conserved cysteine residue at position 83 (numbering scheme of the 140-residue form of FGF-1). Sequence and structure information suggests that this position is a free cysteine in 16 members and participates as a half-cystine in at least 3 (and perhaps as many as 6) other members. While a structural role as a half-cystine provides a stability basis for possible selective pressure, it is less clear why this residue is conserved as a free cysteine (although free buried thiols can limit protein functional half-life). To probe the structural role of the free cysteine at position 83 in FGF-1, we constructed Ala, Ser, Thr, Val, and Ile mutations and determined their effects on structure and stability. These results show that position 83 in FGF-1 is thermodynamically optimized to accept a free cysteine. A second cysteine mutation was introduced into wild-type FGF-1 at adjacent position Ala66, which is known to participate as a half-cystine with position 83 in FGF-8, FGF-19, and FGF-23. Results show that, unlike position 83, a free cysteine at position 66 destabilizes FGF-1; however, upon oxidation, a near-optimal disulfide bond is formed between Cys66 and Cys83, resulting in approximately 14 kJ/mol of increased thermostability. Thus, while the conserved free cysteine at position 83 in the majority of the FGF proteins may have a principal role in limiting functional half-life, evidence suggests that it is a vestigial half-cystine.

Selected figure(s)

Figure 2.
Fig. 2. Relaxed stereo diagram of the X-ray crystal structures (molecule A in the asymmetric unit in each case) of position 83 mutants of FGF-1 (CPK coloring) showing the structural details adjacent to the site of mutation and overlaid with the coordinates of wild-type FGF-1 (PDB code 1JQZ; light gray). (a) Cys83 → Ala. (b) Cys83 → Ser. (c) Cys83 → Thr. (d) Cys83 → Val. (e) Cys83 → Ile.

Figure 3.
Fig. 3. Relaxed stereo diagram of the X-ray crystal structures of the reduced and oxidized forms of the Ala66 → Cys mutant (CPK coloring). (a) Molecule A in the asymmetric unit of reduced Ala66 → Cys overlaid with wild-type FGF-1 (PDB code 1JQZ; light gray). (b) Molecule B in the asymmetric unit of reduced Ala66 → Cys overlaid with wild-type FGF-1 (PDB code 1JQZ; light gray). (c) Molecule A of oxidized Ala66 → Cys overlaid with wild-type FGF-1 (PDB code 1JQZ; light gray). (d) Molecule A of oxidized Ala66 → Cys overlaid with FGF-23 (PDB code 2P39; light gray), which contains Cys at equivalent position Cys66 in FGF-1 and forms a disulfide with Cys at equivalent position Cys83.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 393, 128-139) copyright 2009.

Figures were selected by an automated process.