6ox5

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A SETD3 Mutant (N255A) in Complex with an Actin Peptide with His73 Replaced with Lysine

Structural highlights

6ox5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.098Å
Ligands:EDO, SAH
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ACTB_HUMAN Defects in ACTB are a cause of dystonia juvenile-onset (DYTJ) [MIM:607371. DYTJ is a form of dystonia with juvenile onset. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYTJ patients manifest progressive, generalized, dopa-unresponsive dystonia, developmental malformations and sensory hearing loss.[1] Defects in ACTB are the cause of Baraitser-Winter syndrome type 1 (BRWS1) [MIM:243310. A rare developmental disorder characterized by the combination of congenital ptosis, high-arched eyebrows, hypertelorism, ocular colobomata, and a brain malformation consisting of anterior-predominant lissencephaly. Other typical features include postnatal short stature and microcephaly, intellectual disability, seizures, and hearing loss.[2]

Function

ACTB_HUMAN Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Publication Abstract from PubMed

SETD3 is an actin histidine-N3 methyltransferase, whereas other characterized SET-domain enzymes are protein lysine methyltransferases. We report that in a pre-reactive complex SETD3 binds the N3-protonated form (N3-H) of actin His73, and in a post-reactive product complex, SETD3 generates the methylated histidine in an N1-protonated (N1-H) and N3-methylated form. During the reaction, the imidazole ring of His73 rotates ~105 degrees , which shifts the proton from N3 to N1, thus ensuring that the target atom N3 is deprotonated prior to the methyl transfer. Under the conditions optimized for lysine deprotonation, SETD3 has weak lysine methylation activity on an actin peptide in which the target His73 is substituted by a lysine. The structure of SETD3 with Lys73-containing peptide reveals a bent conformation of Lys73, with its side chain aliphatic carbons tracing along the edge of imidazole ring and the terminal epsilon-amino group occupying a position nearly identical to the N3 atom of unmethylated histidine.

Structural basis for the target specificity of actin histidine methyltransferase SETD3.,Dai S, Horton JR, Woodcock CB, Wilkinson AW, Zhang X, Gozani O, Cheng X Nat Commun. 2019 Aug 6;10(1):3541. doi: 10.1038/s41467-019-11554-6. PMID:31388018[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
4 reviews cite this structure
Regulation of actin isoforms in cellular and developmental processes.
Kashina et al. (2020)
3 more
8 other articles
No citations found

See Also

References

  1. ↑ Procaccio V, Salazar G, Ono S, Styers ML, Gearing M, Davila A, Jimenez R, Juncos J, Gutekunst CA, Meroni G, Fontanella B, Sontag E, Sontag JM, Faundez V, Wainer BH. A mutation of beta -actin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia. Am J Hum Genet. 2006 Jun;78(6):947-60. Epub 2006 Apr 21. PMID:16685646 doi:S0002-9297(07)63917-2
  2. ↑ Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4, S1-2. doi: 10.1038/ng.1091. PMID:22366783 doi:10.1038/ng.1091
  3. ↑ Dai S, Horton JR, Woodcock CB, Wilkinson AW, Zhang X, Gozani O, Cheng X. Structural basis for the target specificity of actin histidine methyltransferase SETD3. Nat Commun. 2019 Aug 6;10(1):3541. doi: 10.1038/s41467-019-11554-6. PMID:31388018 doi:http://dx.doi.org/10.1038/s41467-019-11554-6

Contents


PDB ID 6ox5

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OCA

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