ERLN (endoregulin, SMIM6; UniProt P0DI80) - review notes

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

Human ERLN, 62 aa, single predicted TM helix (UniProt TRANSMEM 25..45), cytosolic
N-terminus, short luminal C-terminal tail. Former symbols C17orf110, SMIM6. Mouse
ortholog Q3U0I6 (Elnl / 1110017F19Rik), 56 aa.
GOA (human): only two rows, both GO:0005789 ER membrane (IEA from UniProt SubCell;
ISS from mouse Q3U0I6). PAN-GO: no IBA. No human MF or BP annotation at all.
Mouse Q3U0I6 GOA: IDA ER membrane, IPI protein binding (SERCA2b), IDA
acts_upstream_of_or_within GO:1901895 negative regulation of ATPase-coupled calcium
transmembrane transporter activity - all from PMID:27923914.

Found by screening the mouse genome for the SERCA-binding motif
PMID:27923914.
ER colocalisation with SERCA2b in COS-7 cells
PMID:27923914.
Co-IP with SERCA2b, competed by PLN (same binding groove)
PMID:27923914.
Ca uptake: lowers apparent Ca affinity (KCa) of SERCA3a, no Vmax change
PMID:27923914.
Expression: non-muscle epithelia, overlapping SERCA3
PMID:27923914.
All constructs in this paper are mouse (mouse genome screen, 56-aa ELN).

PMID:34445594 (Rathod et al. 2021 IJMS, Young lab): recombinant HUMAN ELN
PMID:34445594
co-reconstituted with purified rabbit SERCA1a
PMID:34445594
lowers Vmax, not KCa
PMID:34445594.
This is a purified two-component system: direct evidence that the human peptide itself
inhibits the pump. Note the mechanistic discrepancy with the mouse data (KCa effect on
SERCA3a in cell homogenates vs Vmax effect on SERCA1a in proteoliposomes); both are
inhibitory. The authors themselves note the isoform caveat
PMID:34445594.
PMID:36523160 (Phillips et al. 2023 Biophys J, Robia lab): human sequences
PMID:36523160;
ELN homo- and hetero-oligomerises with PLN, SLN, ALN, DWORF (FRET in cells). This is
the source of UniProt's SUBUNIT annotation (ECO:0000269).
PMID:31449798 (Singh et al. 2019 JMB, Robia lab): micropeptides incl. ELN oligomerise
but bind SERCA as monomers
PMID:31449798.
Species of the ELN construct is not stated in the cached text; the 2023 paper later
comments that mouse sequences are satisfactory models, implying earlier work used mouse.
PMID:39921961 (Cunningham et al. 2025 Cell Calcium; abstract only): ELN lowers ER Ca2+
content in live cells
PMID:39921961.
Species of construct not stated in abstract.

PLN (P26678): GO:0042030 ATPase inhibitor activity IDA/IBA/ISS/IEA; GO:0004857 ISS;
GO:0051117 ATPase binding ISS; GO:1901894 etc.
SLN (O00631): GO:0004857 enzyme inhibitor activity ISS; GO:1901895 IDA; GO:1901894 IDA.
So the SERCA-inhibitory regulins carry an inhibitor MF and a negative regulation of
ATPase-coupled calcium transporter activity BP. ERLN is in the same role (the peptide
itself binds and inhibits the pump) - participation test is satisfied: ELN is the
regulator performing the regulatory step, not a substrate.

Both ER membrane rows: ACCEPT (mouse IDA + human localisation consistent).
NEW MF GO:0042030 ATPase inhibitor activity (IDA, PMID:34445594 human peptide,
purified system; mouse data corroborate). Considered GO:0141110 transporter inhibitor
activity, but PLN precedent and the assay (ATPase turnover) favour GO:0042030.
NEW BP GO:1901895 negative regulation of ATPase-coupled calcium transmembrane
transporter activity (mirrors mouse IDA and SLN IDA).
Not proposed: identical protein binding (homo-oligomerisation) - binding-only term,
functional significance unclear; ER calcium ion homeostasis - only abstract-level
live-cell data; tissue-level processes - none established.