Influence of WFIKKN1 on BMP1-mediated activation of latent myostatin

Area of Science:

• Biochemistry
• Molecular Biology
• Protein Interactions

Background:

• The WFIKKN1 protein interacts with myostatin prodomain, but its functional role in myostatin regulation was unclear.
• WFIKKN1 is a known myostatin antagonist, suggesting a role in modulating myostatin activity.

Purpose of the Study:

• To investigate the mechanism by which WFIKKN1 influences myostatin processing.
• To determine if WFIKKN1 inhibits or enhances the release of active myostatin.

Main Methods:

• Assessed the effect of WFIKKN1 on promyostatin processing by furin.
• Measured the rate of latent myostatin cleavage by bone morphogenetic protein 1 (BMP1) in the presence and absence of WFIKKN1 and heparin.
• Utilized homology modeling to analyze the structure of latent myostatin and potential BMP1 cleavage sites.
• Investigated the role of the KKN1 fragment generated from WFIKKN1 cleavage by BMP1.

Main Results:

• WFIKKN1 did not affect promyostatin processing by furin.
• WFIKKN1 significantly enhanced the cleavage of latent myostatin by BMP1.
• Heparin superstimulated the BMP1-enhancing activity of WFIKKN1.
• BMP1 cleaved WFIKKN1, generating a KKN1 fragment that was primarily responsible for the enhancer activity.
• Homology modeling suggested that KKN1 facilitates BMP1 access to latent myostatin's buried cleavage sites by altering its conformation.
• Heparin's super-enhancement is attributed to increased local concentrations of KKN1, latent myostatin, and BMP1.

Conclusions:

• WFIKKN1 acts as a positive regulator, not an inhibitor, of latent myostatin activation by enhancing its cleavage by BMP1.
• The KKN1 fragment of WFIKKN1 is the key mediator of this BMP1-enhancing activity.
• Heparin plays a crucial role in potentiating the interaction between WFIKKN1, latent myostatin, and BMP1, likely through co-concentration effects.