MYL2 (human, P10916) notes

2026-10-20 — Full re-review, independent of the ProtNLM2 predictions

This is a new review, written as the experimentally characterised reference for the
paralog MYL10 (Q9BUA6). No ProtNLM2 output was consulted.

Deep research

just deep-research-falcon human MYL2 --fallback perplexity-lite failed: falcon
returned "Failed to authenticate", and the perplexity fallback returned HTTP 401
(insufficient quota). No deep-research file exists. The review uses the GOA-cited
papers (cached via just fetch-gene-pmids) and the mouse papers behind the
ortholog annotations, which I fetched by hand: PMID:9422794, 16908724, 10409661,
1379240, 8777429, 15308581, 11356630.

Evolutionary placement

• PANTHER PTHR23049:SF9, "MYOSIN REGULATORY LIGHT CHAIN 2, VENTRICULAR_CARDIAC MUSCLE
  ISOFORM" (from panther.obo). MYL10 is in SF36 and MYL7 (atrial) in SF39.
• IBA nodes on MYL2:
• PTN000549442 (sarcomeric RLCs: MYL2, MYL7, MYLPF, MYL10) carries calcium ion
  binding, with MYL2 as the experimental donor (IDA, PMID:11102452).
• PTN002746142 (MYL2 branch; donors mouse Myl2 MGI:97272, rat RGD:1564245 and
  human) carries heart development, myofibril, cardiac muscle contraction and
  muscle cell fate specification.
• PTN001495767 is a deep node that carries cytoplasm.
• I checked the mouse Myl2 (P51667) GOA rows in QuickGO. The relevant experimental
  donors are: KO with defective ventricular sarcomere assembly PMID:9422794; RLC
  phosphorylation increasing calcium sensitivity and force PMID:16908724; nonphosphorylatable MLC2v transgenic mice PMID:10409661. The muscle
  cell fate specification donor is PMID:1379240, a promoter-luciferase study of
  MLC-2 expression and not a fate experiment. I therefore REMOVED that IBA.
• Mouse and rat Myl2 are one-to-one orthologs in SF9, so transferring the mouse
  physiology to human MYL2 is evolutionarily grounded.

What is experimentally established in human, and what is inferred

The following come from experiments on the human protein or from human genetics:
- Ca2+ binding by recombinant human RLC, altered by HCM mutations and by
phosphorylation PMID:11102452.
- Binding of recombinant human MLC2 to the myosin heavy chain, S1 and myofibrils
PMID:8287067.
- Recessive loss of function causes lethal infantile myopathy with cardiomyopathy
[PMID:23365102, PMID:32453731]. Wild-type human MYL2 partially rescues
Drosophila Mlc2-knockdown heart function PMID:32453731.
- GFP-MYL2 localizes along the cytoskeleton of H9c2 cells PMID:32453731. MYL2
is quantified as a myofilament protein in human cardiac tissue PMID:25771144.
- Cardiac-MLCK (MYLK3) phosphorylates MLC2v PMID:17885681.

The following are inferred from mouse or rat orthologs:
- Phosphorylation-dependent positive regulation of force, Ca2+ sensitivity and
stretch activation.
- The requirement for ventricular sarcomere assembly.
- The A-band location (the UniProt statement is by similarity to rat).

Annotation problems found

• Actin monomer binding (IDA, PMID:9180271). The abstract describes N-terminal
  peptides of the essential light chains (ALC-1/VLC-1, i.e. MYL4/MYL3) and does
  not mention RLC. This is probably a VLC-1/MLC-2v name confusion. Marked UNDECIDED
  because the cached record is abstract-only.
• Cytoskeleton and actin cytoskeleton (IDA, PMID:17043135). I read the full text.
  Staining used Thr18/Ser19 phospho-MLC2 antibodies in MG63 and other non-muscle
  cells, which detect the nonmuscle RLCs MYL9/MYL12. The cytoskeleton row is
  MODIFY, consistent with the true claim, with the evidence problem stated in the
  reason. The actin cytoskeleton colocalizes_with row is UNDECIDED.
• Negative regulation of cell growth (PMID:15824735) is based on ectopic
  expression in RCC cells. MARK_AS_OVER_ANNOTATED.
• Ventricular cardiac muscle tissue morphogenesis (IMP, PMID:8673105) records an
  HCM phenotype, which is downstream of MYL2's function. MARK_AS_OVER_ANNOTATED.
• Cytosol (ARBA plus Reactome compartment convention): MYL2 sits in thick
  filaments, so MARK_AS_OVER_ANNOTATED.
• General terms were refined to terms the gene already carries: heart development
  to cardiac myofibril assembly; cytoplasm, myofibril and sarcomere to A band;
  myosin complex and cytoskeleton to muscle myosin complex; heart contraction to
  cardiac muscle contraction; regulation of force to positive regulation of
  force. Actin filament-based movement became muscle filament sliding, and
  myosin heavy chain binding became myosin II heavy chain binding.
• The four generic protein binding IPIs (MYOC, USP6, IRX6, PSORS1C2) were
  REMOVED under the protein-binding policy.

Notes for transfer to MYL10

The only MYL2 function that PAINT propagated to the node shared with MYL10 is
calcium ion binding. Heart, myofibril, contraction and myosin-heavy-chain terms
sit on the MYL2 branch (PTN002746142) or elsewhere, and were not propagated to
SF36. They should not be transferred to MYL10 on the basis of this review.