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Defining Histone-modifying Complexes

A variety of post-translational modifications of nucleosomal histones contribute to gene regulation. One such modification, methylation of histone H3 on lysine 4 (H3 K4), is associated with regions of active transcription. The yeast Set1-containing complex, COMPASS, was the first histone H3 K4 methyltransferase to be described. The mammalian Set1 homologue, MLL, also exists in a COMPASS-like complex that methylates H3 K4. Although there is only one Set1 in yeast, there are several MLL-related proteins in higher eukaryotic organisms. The MLL family of histone methyltransferases plays a key role in the regulation of gene expression and is an important regulator of developmental processes in metazoa.

Despite intense interest the composition of MLL complexes has remained controversial. In this Paper of the Week, Young-Wook Cho and colleagues have defined MLL complexes and, in the process, have largely resolved controversies over the nature of the complexes. They show that complexes containing different MLL family members contain a COMPASS-like backbone but distinct sets of proteins specific to each version of MLL. In particular, their data indicate that MLL3 and MLL4 complexes include a submodule that includes PTIP, a protein that has been implicated in the response to DNA damage but whose biochemical function has remained unclear.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 20395-20406

A Kinase's Role in Muscle Contraction

When fast-twitch skeletal muscle is stimulated repeatedly, contraction force is enhanced. This force potentiation is caused by the phosphorylation of myosin regulatory light chain (RLC) by Ca²⁺/calmodulin (CaM)-dependent myosin light chain kinase (skMLCK).

Activation of skMLCK was measured by FRET.

In this Paper of the Week, Jeffrey W. Ryder and colleagues generated transgenic mice that express rabbit skMLCK fused to a CaM biosensor in fast- and slow-twitch skeletal muscle. They showed that skMLCK is a limiting factor for RLC phosphorylation and twitch force potentiation in fast-twitch muscle and that phosphorylation of skeletal RLC enhances twitch force potentiation only in one kind of fast-twitch muscle cell. Using fluorescence resonance energy transfer (FRET) analyses, they report that CaM is not limiting to frequency-dependent activation of the kinase in intact muscle. Most importantly, the slow rate of kinase inactivation provides a biochemical memory for the physiological responses. This work provides new insights into regulation of striated muscle contraction by myosin light chain phosphorylation and will be of interest to scientists investigating the biochemistry of muscle contraction, Ca²⁺/calmodulin-dependent processes, and kinase regulation.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 20447-20454

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