PDBsum entry 3hh2

Signaling protein/cytokine

PDB id

3hh2

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Contents

			Protein chains

					109 a.a. *


					278 a.a. *

			Ligands

					PO4 ×3


					CIT ×2

			Waters ×349

* Residue conservation analysis

PDB id:

3hh2

Links

Name:

Signaling protein/cytokine

Title:

Crystal structure of the myostatin:follistatin 288 complex

Structure:

Growth/differentiation factor 8. Chain: a, b. Fragment: unp residues 268-376. Synonym: gdf-8, myostatin. Engineered: yes. Follistatin. Chain: c, d. Fragment: unp residues 30-317. Synonym: fs, activin-binding protein.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: mstn, gdf8. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho. Homo sapiens. Human.

Resolution:

2.15Å

R-factor:

0.210

R-free:

0.249

Authors:

J.N.Cash,T.B.Thompson

Key ref:

J.N.Cash et al. (2009). The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding. Embo J, 28, 2662-2676. PubMed id: 19644449

Date:

14-May-09

Release date:

04-Aug-09

PROCHECK

	Headers

	References

Protein chains

O08689 (GDF8_MOUSE) - Growth/differentiation factor 8 from Mus musculus

Seq: Struc:					376 a.a. 109 a.a.

Protein chains

P19883 (FST_HUMAN) - Follistatin from Homo sapiens

Seq: Struc:					344 a.a. 278 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

	Embo J 28:2662-2676 (2009)
PubMed id: 19644449

The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.
J.N.Cash, C.A.Rejon, A.C.McPherron, D.J.Bernard, T.B.Thompson.

ABSTRACT

Myostatin is a member of the transforming growth factor-beta (TGF-beta) family and a strong negative regulator of muscle growth. Here, we present the crystal structure of myostatin in complex with the antagonist follistatin 288 (Fst288). We find that the prehelix region of myostatin very closely resembles that of TGF-beta class members and that this region alone can be swapped into activin A to confer signalling through the non-canonical type I receptor Alk5. Furthermore, the N-terminal domain of Fst288 undergoes conformational rearrangements to bind myostatin and likely acts as a site of specificity for the antagonist. In addition, a unique continuous electropositive surface is created when myostatin binds Fst288, which significantly increases the affinity for heparin. This translates into stronger interactions with the cell surface and enhanced myostatin degradation in the presence of either Fst288 or Fst315. Overall, we have identified several characteristics unique to myostatin that will be paramount to the rational design of myostatin inhibitors that could be used in the treatment of muscle-wasting disorders.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20545624

C.C.Rider, and B.Mulloy (2010).
Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.

Biochem J, 429, 1.

20161792

C.S.Starck, and A.J.Sutherland-Smith (2010).
Cytotoxic aggregation and amyloid formation by the myostatin precursor protein.

PLoS One, 5, e9170.

21423813

S.J.Lee (2010).
Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass.

Immunol Endocr Metab Agents Med Chem, 10, 183-194.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.