MRLN (myoregulin, P0DMT0) — curation notes

2026-09-30 — initial review (claude-code)

46-aa single-pass (type II; N-terminus cytosolic, 3 C-terminal residues lumenal) transmembrane
micropeptide encoded in exon 3 of a transcript previously annotated as a lncRNA (LINC00948 in human).
PMID:25640239
PMID:25640239
Human vs mouse sequence (UniProt FASTA, fetched 2026-09-30):
human P0DMT0 MTGKNWILISTTTPKSLEDEIVGRLLKILFVIFVDLISIIYVVITS
mouse Q9CV60 MSGKSWVLISTTSPQSLEDEILGRLLKILFVLFVDLMSIMYVVITS
The SERCA-binding hydrophobic motif residues mutated in mouse (L29, F30, F33) and the
unusual TM Asp35 and Lys27 are all conserved in human. ISS transfer is well justified.
UniProt: TCDB 1.A.50.3.1 (phospholamban family); InterPro IPR049526; PAN-GO: 0 annotations
(no PANTHER family/IBA coverage).
HPA: tissue enhanced in skeletal muscle and tongue.

Co-localises with SERCA1 in SR of adult mouse muscle (GFP-MLN electroporation), SR/ER fraction
in C2C12. PMID:25640239
Co-IP with SERCA1, SERCA2a, SERCA2b; L29A/F30A/F33A abolish binding.
PMID:25640239
Ca-ATPase assay in HEK293 homogenates: increased KCa, no Vmax change.
PMID:25640239
KO mouse: increased SR Ca2+ and ~31% longer treadmill running.
PMID:25640239
Mechanistic discrepancy: in co-reconstituted proteoliposomes with rabbit SERCA1a and synthetic MLN
(Young / Espinoza-Fonseca labs), MLN lowers Vmax without changing KCa.
PMID:34445594
PMID:37014032
PMID:37918638
Species of the synthetic MLN peptide is not stated in the cached text of these papers
(34445594 states MD models used "Full-length human MLN"). Either way, inhibition of the pump is
consistent; only the kinetic mechanism (KCa vs Vmax) differs. UniProt's human FUNCTION text says
"decreasing the apparent affinity of the ATPase for Ca(2+)" — this is contested by the reconstitution data.
FRET/co-IP: homo-oligomerises but binds SERCA as a monomer.
PMID:31449798
Family context: MLN/PLN/SLN share the SERCA-binding motif; ALN/ELN in non-muscle cells.
PMID:27923914
Evolution: regulins related to FXYD; MRLN in CCDC6–SLC16A9 neighbourhood.
PMID:28436536

Human DMD immortalized myotubes / myoblasts: MLN shRNA improves SR Ca2+ content; NR1D1 represses
MLN transcription. PMID:35917173
PMID:35917173
Human AC16 cardiomyocyte line: MLN knockdown raises SERCA2a activity.
PMID:41348974
Caveat: AC16 is a transformed hybrid line; MLN is not normally a cardiac peptide
(PMID:25640239 reported no cardiac expression in mouse). Supports human SERCA inhibition
by endogenous MLN, but physiological cardiac relevance is uncertain.
Human heart mRNA and rat Langendorff (PMID:38246425, abstract only; preliminary).

GOA human has 7 rows: enzyme inhibitor activity (ISS, IEA), ER membrane (IEA is_active_in),
SR membrane (ISS, IEA), negative regulation of calcium ion import into SR (ISS).
Mouse Q9CV60 source annotations: GO:0004857 IDA (UniProt), GO:1902081 IDA/IMP, GO:1901895 IDA
(PMID:27923914), GO:0033017 IDA, GO:0005789 IDA, protein binding IPI.
Comparators: human PLN (P26678) has GO:0042030 ATPase inhibitor activity (IDA+IBA) and
GO:0141110 transporter inhibitor activity (IDA); SLN (O00631) has GO:0004857 ISS and
GO:1901895 IDA. The mouse Pln GO-CAM (gocams 62f58d8800005094) types Pln's activity as
GO:0042030 ATPase inhibitor activity in ER membrane.
Ontology note: GO:0005388 P-type calcium transporter activity is NOT a descendant of
catalytic activity / ATP hydrolysis activity in current GO (is_a transporter + ATP-dependent
activity). So GO:0004857 "enzyme inhibitor activity" (reduces a catalytic activity) is a
loose fit; GO:0042030 ATPase inhibitor activity is what curators use for PLN (IBA, GO-CAM)
and is directly supported by ATPase assays. MODIFY → GO:0042030.
GO:1901895 negative regulation of ATPase-coupled calcium transmembrane transporter activity:
MLN performs the inhibition itself (direct binding to SERCA), passes the participation test;
comparators PLN and SLN (same role) both carry it by IDA. Propose NEW (IMP, human AC16 data).
GO-CAM: no model in gocams/index.tsv contains MRLN/P0DMT0 (checked 2026-09-30).