6MAA

WFIKKN2 Follistatin Domain

6MAA の概要

• エントリーDOI: 10.2210/pdb6maa/pdb
• 分子名称: WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2, NITRATE ION (3 entities in total)
• 機能のキーワード: wfikkn2, gasp, kazal, follsitatin, peptide binding protein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10322.43

構造登録者

McCoy, J.C.,Walker, R.G.,Thomas, T.B. (登録日: 2018-08-27, 公開日: 2019-03-06, 最終更新日: 2024-10-30)

主引用文献

McCoy, J.C.,Walker, R.G.,Murray, N.H.,Thompson, T.B.
Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11.
J.Biol.Chem., 294:6333-6343, 2019

PubMed Abstract: Growth differentiation factor 8 (GDF8; also known as myostatin) and GDF11 are closely related members of the transforming growth factor β (TGF-β) family. GDF8 strongly and negatively regulates skeletal muscle growth, and GDF11 has been implicated in various age-related pathologies such as cardiac hypertrophy. GDF8 and GDF11 signaling activities are controlled by the extracellular protein antagonists follistatin; follistatin-like 3 (FSTL3); and WAP, follistatin/kazal, immunoglobulin, Kunitz, and netrin domain-containing (WFIKKN). All of these proteins contain a follistatin domain (FSD) important for ligand binding and antagonism. Here, we investigated the structure and function of the FSD from murine WFIKKN2 and compared it with the FSDs of follistatin and FSTL3. Using native gel shift and surface plasmon resonance analyses, we determined that the WFIKKN2 FSD can interact with both GDF8 and GDF11 and block their interactions with the type II receptor activin A receptor type 2B (ActRIIB). Further, we solved the crystal structure of the WFIKKN2 FSD to 1.39 Å resolution and identified surface-exposed residues that, when substituted with alanine, reduce antagonism of GDF8 in full-length WFIKKN2. Comparison of the WFIKKN2 FSD with those of follistatin and FSTL3 revealed differences in both the FSD structure and position of residues within the domain that are important for ligand antagonism. Taken together, our results indicate that both WFIKKN and follistatin utilize their FSDs to block the type II receptor but do so via different binding interactions.

PubMed: 30814254
DOI: 10.1074/jbc.RA118.005831

実験手法

X-RAY DIFFRACTION (1.394 Å)