8QSU

Crystal structure of SPOUT1/CENP-32 bound to SAH

Summary for 8QSU

• Entry DOI: 10.2210/pdb8qsu/pdb
• Descriptor: Putative methyltransferase C9orf114, S-ADENOSYL-L-HOMOCYSTEINE (2 entities in total)
• Functional Keywords: spout rna methyltransferase spindle organisation chromosome missegregation cell viability, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34163.11

Authors

Jeyaprakash, A.A.,Abad, M.A. (deposition date: 2023-10-11, release date: 2024-10-23, Last modification date: 2025-05-28)

Primary citation

Dharmadhikari, A.V.,Abad, M.A.,Khan, S.,Maroofian, R.,Sands, T.T.,Ullah, F.,Samejima, I.,Shen, Y.,Wear, M.A.,Moore, K.E.,Kondakova, E.,Mitina, N.,Schaub, T.,Lee, G.K.,Umandap, C.H.,Berger, S.M.,Iglesias, A.D.,Popp, B.,Abou Jamra, R.,Gabriel, H.,Rentas, S.,Rippert, A.L.,Gray, C.,Izumi, K.,Conlin, L.K.,Koboldt, D.C.,Mosher, T.M.,Hickey, S.E.,Albert, D.V.F.,Norwood, H.,Lewanda, A.F.,Dai, H.,Liu, P.,Mitani, T.,Marafi, D.,Eker, H.K.,Pehlivan, D.,Posey, J.E.,Lippa, N.C.,Vena, N.,Heinzen, E.L.,Goldstein, D.B.,Mignot, C.,de Sainte Agathe, J.M.,Al-Sannaa, N.A.,Zamani, M.,Sadeghian, S.,Azizimalamiri, R.,Seifia, T.,Zaki, M.S.,Abdel-Salam, G.M.H.,Abdel-Hamid, M.S.,Alabdi, L.,Alkuraya, F.S.,Dawoud, H.,Lofty, A.,Bauer, P.,Zifarelli, G.,Afzal, E.,Zafar, F.,Efthymiou, S.,Gossett, D.,Towne, M.C.,Yeneabat, R.,Perez-Duenas, B.,Cazurro-Gutierrez, A.,Verdura, E.,Cantarin-Extremera, V.,Marques, A.D.V.,Helwak, A.,Tollervey, D.,Wontakal, S.N.,Aggarwal, V.S.,Rosenfeld, J.A.,Tarabykin, V.,Ohta, S.,Lupski, J.R.,Houlden, H.,Earnshaw, W.C.,Davis, E.E.,Jeyaprakash, A.A.,Liao, J.
RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.
Nat Commun, 16:1703-1703, 2025

PubMed Abstract: SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

PubMed: 39962046
DOI: 10.1038/s41467-025-56876-w

Experimental method

X-RAY DIFFRACTION (2.38 Å)