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UniProt release 2019_05

Published June 5, 2019

Headline

Love’s Labour (nearly) Lost

Actin is a globular multi-functional protein that forms microfilaments. It is probably one of the most abundant proteins in our cells, and in almost all eukaryotic cells. Actin plays crucial roles in many processes essential to life, such as cell migration and division, and muscle contraction. Actin undergoes several post-translational modifications thought to control its cellular functions. Among them is histidine methylation, a rare modification in vertebrates that affects only a few proteins, but which was reported to occur in actin over a half-century ago. Two recent publications revealed the identity of the enzyme catalyzing this methylation, namely a SET domain-containing protein called SETD3. This is not only the first actin methylase, but also the first histidine methylase to be identified in vertebrates.

SETD3 had previously been reported to be a methylase, but a histone methyltransferase, modifying essentially lysine residues. This observation was consistent with the well-established role of SET domain-containing proteins in histone methylation on lysine residues. Consistent, yes, but erroneous! SETD3 actually methylates only actin and only at histidine-73 (His-73). Structural studies showed that the catalytic pocket so perfectly fits the actin peptide, with an extensive network of interactions, that accommodation of divergent sequences may be quite inefficient. From a functional point view, His-73 methylation modestly accelerates the assembly of actin filaments and somewhat reduces the nucleotide-exchange rate on actin monomers. SETD3 knockout mice are viable and overall healthy, in spite of several moderate phenotypes, including some skeletal muscle myopathy, abnormal cardiac electrocardiogram and mildly decreased lean mass. So what? One could think that SETD3-catalyzed histidine methylation of actin is not so important after all, if not for the observation that litter sizes of homozygous knockout females are significantly smaller than litters from wild-type or heterozygous females. This is due to incomplete delivery, with fetuses remaining in utero. The mutant females experience uterus contraction problems that are not improved by oxytocin administration. In vitro SETD3-depleted human myometrial cells also have impeded signal-induced contractions by oxytocin and endothelin-1/EDN1, supporting a role for His-73 methylation in uterine smooth muscle cell contraction during parturition.

The UniProtKB/Swiss-Prot SETD3 entries have been updated and are publicly available as of this release.

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Changes to the controlled vocabulary of human diseases

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Deleted diseases

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  • Macrocephaly, macrosomia, facial dysmorphism syndrome.
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