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Structure paper

TitleStructural mechanisms of SAMD9 autoinhibition and pathogenic dysregulation.
Journal, issue, pagesSci Adv, Vol. 12, Issue 39, Page eaeg3967, Year 2026
Publish dateSep 25, 2026
AuthorsZongjun Mou / Fushun Zhang / Marisol Morales / Bibekananda Sahoo / Xinghong Dai / Yan Xiang /
PubMed AbstractSAMD9 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 ...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.
External linksSci Adv / PubMed:42777028 / PubMed Central
MethodsEM (single particle)
Resolution2.53 - 3.6 Å
Structure data

74339

9zjr

EMDB-74339, PDB-9zjr:
Human sterile alpha motif domain-containing protein 9 (SAMD9), monomer
Method: EM (single particle) / Resolution: 2.53 Å

74340

9zjs

EMDB-74340, PDB-9zjs:
Human sterile alpha motif domain-containing protein 9 (SAMD9), asymmetric dimer "shell" shape
Method: EM (single particle) / Resolution: 3.04 Å

74342

9zju

EMDB-74342, PDB-9zju:
Human sterile alpha motif domain-containing protein 9 (SAMD9), symmetric dimer
Method: EM (single particle) / Resolution: 2.6 Å

74343

9zjv

EMDB-74343, PDB-9zjv:
Human sterile alpha motif domain-containing protein 9 (SAMD9), asymmetric dimer "wing" shape
Method: EM (single particle) / Resolution: 3.13 Å

74344

9zjw

EMDB-74344, PDB-9zjw:
Human sterile alpha motif domain-containing protein 9 (SAMD9), loss-of-function mutant R837A
Method: EM (single particle) / Resolution: 2.8 Å

74347

9zjz

EMDB-74347, PDB-9zjz:
Human sterile alpha motif domain-containing protein 9 (SAMD9), loss-of-function mutant R685Q/G686C/I968C
Method: EM (single particle) / Resolution: 2.87 Å

78192

37ht

EMDB-78192, PDB-37ht:
Human sterile alpha motif domain-containing protein 9 (SAMD9), loss-of-function mutant R1562E/I1567R/E1568I
Method: EM (single particle) / Resolution: 3.13 Å

78199

37ib

EMDB-78199, PDB-37ib:
Sterile alpha motif domain-containing protein 9, residues 623-1589
Method: EM (single particle) / Resolution: 3.2 Å

78201

37id

EMDB-78201, PDB-37id:
Human sterile alpha motif domain-containing protein 9 (SAMD9), loss-of-function mutant Q514S/R515S/R522S/R553S/Q565S/R593S
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / inflammasome / signal transductionATPases with numerous domains (STAND) / sterile alpha motif. poxvirusrestriction factor / ANTIVIRAL PROTEIN / signal transduction ATPases with numerous domains (STAND) / sterile alpha motif / poxvirus restriction factor / CYTOSOLIC PROTEIN

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