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UniProt release 2016_05

Published May 11, 2016

Headline

Slow/White and the 6 DWORFs

Striated muscle function relies on a cycle of contraction and relaxation. Upon electrical stimulation of the myocyte plasma membrane, Ca(2+) is released from the sarcoplasmic reticulum (SR) into the cytosol. The released calcium activates movement of the molecular motor myosin along actin filaments and contraction occurs. Cytosolic Ca(2+) is then pumped back into the SR, through the action of SERCA proteins, allowing actomyosin relaxation. The SERCA proteins are SR-resident transmembrane ATPases, that couple the hydrolysis of ATP with Ca(2+) translocation.

Recent studies have highlighted a role for a network of (very) small ORFs (smORFs) in SERCA regulation. The first members of this exclusive but growing club were phospholamban (PLN, 52 amino acids) and sarcolipin (SLN, 31 amino acids), which were both isolated by classical biochemical approaches decades ago. Both bind SERCA and reduce the rate of calcium movement in heart and slow skeletal muscle fibers. More recently the SERCA inhibitory micropeptide myoregulin (MRLN, 46 amino acids), was identified in fast muscle fibers by Anderson et al. These authors started by screening for skeletal muscle-specific RNAs and discovered MRLN in an apparent long non-coding RNA (lncRNA). Encouraged by this discovery, Olson lab members continued to look for smORFs in other muscle-specific lncRNAs and found DWORF (34 amino acids), encoded by 2 exons of a 795 bp-long transcript; very difficult to predict using current software. In mouse myocytes, DWORF expression stimulates Ca(2+) uptake in the SR, not by direct activation of SERCA, but rather by relieving MRLN-, PLN- and SLN-mediated inhibition. DWORF expression may be particularly beneficial for recovery from periods of prolonged contraction.

SERCA regulation by micropeptides encoded in supposed lncRNAs is not a vertebrate-specific phenomenon. In Drosophila melanogaster, a single muscle-specific transcript encodes 2 smORFs related to sarcolipin, sarcolamban A and B (SCLA, 28 amino acids, and SCLB, 29 amino acids). Computer simulations predicted that both peptides fit the groove of SERCA, and this has been experimentally verified. While mutant flies deficient in sarcolamban showed no behavioral or morphological muscle phenotype, they do exhibit significantly more arrhythmic cardiac contractions than wild-type flies.

The idea that smORFs may be overlooked in the current genome annotation is not new, and these recent advances in muscle physiology underscore the likelihood that many transcripts annotated as noncoding RNAs may actually encode peptides with important biological functions. These smORFs could represent fast-evolving key regulators of larger molecular complexes. They also highlight the need for expert biocuration to make these data available in databases, as they cannot be automatically predicted, retrieved, nor annotated at the current time.

The 6 dworfs have been curated and integrated into UniProtKB/Swiss-Prot and we continue to survey the literature for other hidden micropeptide treasures (motivated solely by biological interest and not by our desire to find a seventh member for the purposes of this headline).

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