Structure of Myostatin·Follistatin-like 3

Cash, Jennifer N.; Angerman, Elizabeth; Kattamuri, Chandramohan; Nolan, Kristof; Zhao, Huaying; Sidis, Yisrael; Keutmann, Henry T.; Thompson, Thomas B.

doi:10.1074/jbc.m111.270801

Cited by 76 publications

(56 citation statements)

References 57 publications

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“…The molecular structure of MSTN has been extensively investigated, including two X-ray crystal structures of MSTN in complex with two known antagonists 19, 20 . In contrast, GDF11 is less well characterized, and much of what is known for MSTN has been inferred for GDF11.…”

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

“…These include follistatin (FS), follistatin-like 3 (FSTL3), decorin, and growth/differentiation factor associated serum proteins 1 and 2 (GASP1, GASP2) 28, 66-70 . Structural studies indicate that two FS or FSTL3 molecules symmetrically embrace the ligand to block both receptor epitopes 19, 20 . FSTL3 and FS similarly contain an N-terminal domain followed by tandem follistatin domains.…”

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

“…The N-terminal domain binds in the concave Type I receptor slot where GDF11 and MSTN show the highest divergence 19-21 . However, mutagenesis studies and comparison to other FS-ligand structures indicate that the FS N-terminal domain is highly plastic and can accommodate diverse Type I interfaces 19, 20, 71-73 . Therefore, sequence differences likely have minimal impact on GDF11 and MSTN antagonism by FS.…”

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

“…The follistatin domain is the primary driver of ligand antagonism 80 . Despite a similar domain layout, GASP1 binds MSTN in a unique 1:1 ratio, forming an asymmetric complex, whereas GASP2 binds symmetrically in a 2:1 ratio 68 , similar to FS or FSTL3 19, 20, 77 . Interestingly, C-terminal truncation of GASP1 induces 2:1 binding and weaker affinity for MSTN, similar to that of GASP2 77, 79, 80 .…”

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

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Biochemistry and Biology of GDF11 and Myostatin

Walker

Poggioli

Katsimpardi³

et al. 2016

Circulation Research

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172

106

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Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging. (Circ Res.

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Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

Section: Biochemical Regulation Of Gdf11 and Myostatinmentioning

confidence: 99%

See 2 more Smart Citations

Biochemistry and Biology of GDF11 and Myostatin

Walker

Poggioli

Katsimpardi³

et al. 2016

Circulation Research

Self Cite

172

106

View full text Add to dashboard Cite

show abstract

“…While sequence similarity has challenged partitioned detection of GDF11 and MSTN, structural insights suggest that amino acid sequence variation may confer important differences in inhibitory protein and receptor binding affinities (Cash et al, 2012; Cash et al, 2009; Padyana et al, 2016). Furthermore, expression pattern analyses and loss of function studies support non-redundant biological functions (McPherron et al, 1997, 1999; Nakashima et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease

et al. 2016

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Growth and differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in aging processes. We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homologue, myostatin (MSTN), based on unique amino acid sequence features. Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging. Neither GDF11 nor MSTN levels differ as a function of age in healthy women. In an independent cohort of older adults with severe aortic stenosis, we show that individuals with higher GDF11 were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, higher GDF11 at surgical baseline was associated with rehospitalization and multiple adverse events. Cumulatively, our results show that GDF11 levels do not decline throughout aging but are associated with comorbidity, frailty, and greater operative risk in older adults with cardiovascular disease.

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Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Cox

Lidral²,

McCoy

et al. 2019

Human Mutation

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Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

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Structure of Myostatin·Follistatin-like 3

Cited by 76 publications

References 57 publications

Biochemistry and Biology of GDF11 and Myostatin

Biochemistry and Biology of GDF11 and Myostatin

Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

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