37HT

Human sterile alpha motif domain-containing protein 9 (SAMD9), loss-of-function mutant R1562E/I1567R/E1568I

Summary for 37HT

• Entry DOI: 10.2210/pdb37ht/pdb
• EMDB information: 78192
• Descriptor: Sterile alpha motif domain-containing protein 9, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION (3 entities in total)
• Functional Keywords: inflammasome, signal transductionatpases with numerous domains (stand), sterile alpha motif. poxvirusrestriction factor, antiviral protein, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 167263.47

Authors

Mou, Z.,Zhang, F.,Dai, X.,Xiang, Y. (deposition date: 2026-07-21, release date: 2026-08-12, Last modification date: 2026-10-07)

Primary citation

Mou, Z.,Zhang, F.,Morales, M.,Sahoo, B.,Dai, X.,Xiang, Y.
Structural mechanisms of SAMD9 autoinhibition and pathogenic dysregulation.
Sci Adv, 12:eaeg3967-eaeg3967, 2026

PubMed Abstract: SAMD9 and SAMD9L (SAMD9/9L) are large cytosolic proteins essential for hematopoietic homeostasis and antiviral defense (-). Germline gain-of-function (GoF) mutations in SAMD9/9L cause severe multisystem disorders and predispose to leukemia, but the mechanisms that regulate SAMD9/9L activity and how pathogenic mutations disrupt these processes remain poorly understood. Here, we report cryo-electron microscopy structures of human SAMD9 in multiple conformational and oligomeric states. SAMD9 predominantly adopts a closed, autoinhibited conformation stabilized by a central ATP-bound nucleotide-binding oligomerization domain (NOD) and an extensive network of intramolecular interactions. Recurrent patient-derived GoF mutations localize to and destabilize these intramolecular interfaces, whereas structure-guided compensatory mutations that restabilize these interfaces restore autoinhibition. We further identify low-abundance asymmetric SAMD9 dimers in which one protomer undergoes large conformational changes and establishes intermolecular interactions that are essential for SAMD9 activation. Together, these findings define the structural basis of SAMD9 autoinhibition and reveal how human GoF mutations disrupt this regulatory mechanism to drive disease.

PubMed: 42777028
DOI: 10.1126/sciadv.aeg3967

Experimental method

ELECTRON MICROSCOPY (3.13 Å)