Structural Mechanisms of SAMD9 Autoinhibition and Pathogenic Dysregulation

Area of Science:

• Structural Biology
• Molecular Biology
• Genetics

Background:

• SAMD9 and SAMD9L (SAMD9/9L) are crucial for hematopoietic homeostasis and antiviral defense.
• Germline gain-of-function (GoF) mutations in SAMD9/9L are linked to multisystem disorders and leukemia predisposition.
• The regulatory mechanisms of SAMD9/9L activity and the impact of pathogenic mutations are not well understood.

Purpose of the Study:

• To elucidate the structural basis of SAMD9 regulation and the mechanism by which GoF mutations cause disease.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine structures of human SAMD9 in various states.
• Analysis of intramolecular interactions and conformational changes.
• Investigating the effect of patient-derived mutations and compensatory mutations.

Main Results:

• SAMD9 predominantly exists in a closed, autoinhibited conformation stabilized by the nucleotide-binding oligomerization domain (NOD) and intramolecular interactions.
• GoF mutations identified in patients destabilize these critical intramolecular interfaces.
• Compensatory mutations can restore autoinhibition by re-establishing disrupted interactions.
• Low-abundance asymmetric dimers of SAMD9 were identified, featuring significant conformational changes essential for activation.

Conclusions:

• The study defines the structural foundation of SAMD9 autoinhibition.
• It explains how pathogenic GoF mutations disrupt this autoinhibition, leading to disease.
• Findings provide insights into SAMD9/9L-related disorders and potential therapeutic strategies.