STRIT1 (DWORF) review notes

2026-09-30 — initial review (claude-code, MICROPROTEINS project)

UniProt P0DN84 (DWORF_HUMAN), 35 aa, PE1. Single C-terminal TM helix (14-34), NMR
structure 7MPA. HGNC name "small transmembrane regulator of ion transport 1". HPA:
group-enriched in skeletal muscle and tongue.
Encoded by a transcript previously annotated as lncRNA LOC100507537
PMID:26816378.
Mouse ortholog P0DN83 (34 aa). "Unless otherwise noted, further studies focused on the
murine homolog of DWORF" PMID:26816378.
Belongs with PLN, SLN, MRLN (myoregulin), ERLN, ALN (another-regulin) to the "regulin"
SERCA-regulatory micropeptides PMID:28436536.

PMID:26816378
Co-IP with all SERCA isoforms (COS7); binding of PLN/SLN/MLN to SERCA reduced by DWORF.
In COS7 with SERCA2a, DWORF alone did not change Ca affinity: PMID:26816378. Repeated in the DCM mouse paper PMID:30299255.
KO soleus: decreased SERCA Ca affinity; slowed post-tetanic relaxation PMID:26816378.
Localization: GFP-DWORF in SR-like striations in FDB fibres, ER in COS7.
Human data in that paper is only expression: PMID:26816378.

Li et al. 2021 JBC used the human DWORF and human SERCA2a in HEK293 cells:
PMID:33581112
Ca-ATPase assays: PMID:33581112
Dual mechanism: PMID:33581112
Mutagenesis: PMID:33581112
Fisher et al. 2021 eLife: purified recombinant human DWORF co-reconstituted with rabbit
SERCA1a increases turnover [PMID:34075877 "Recombinant human DWORF was expressed as a maltose-binding protein (MBP) fusion with a TEV cleavage site for removal of MBP."; "Here, we show that DWORF is a direct activator of SERCA, increasing its turnover rate in the absence of phospholamban."]
Phillips et al. 2023: human sequences, FRET; homo- and hetero-oligomers with PLN, SLN,
ALN, ELN PMID:36523160.
Cleary et al. 2022: DWORF binds E1P/E2P states preferentially PMID:35605666; Bovo 2024:
PLN phosphorylation promotes DWORF activation in HEK293 with human SERCA2a PMID:38823350.
Fisher 2025: Leu12/Pro15 required; P15 substitutions turn DWORF into an inhibitor PMID:40910871.
So: the "direct activation" question is disputed between labs (Olson: displacement only;
Thomas/Young/Robia: direct activation plus displacement). Both mechanisms give net SERCA
activation, so an activator-of-transporter MF holds regardless.

Human GOA: 45 IPI protein binding, all from HuRI Y2H (PMID:32296183). None of the 45
partners is SERCA or a regulin; nearly all are membrane proteins (aquaporins, tetraspanins,
SLCs, GPCRs, syntaxins, BSCL2) — the typical sticky-TM-helix pattern of Y2H. REMOVE all
(uninformative; not claiming false).
Function rows (enzyme activator activity, regulation of ATPase-coupled Ca transporter
activity, positive regulation of Ca import into SR, regulation of slow-twitch contraction,
SR membrane) are all ISS from mouse P0DN83 (whose own annotations are IDA/IMP from
PMID:26816378/30299255). The human IDA-grade evidence (PMID:33581112, 34075877) was never
used by GO curators — UniProt uses it in the FUNCTION comment (ECO:0000269) but GO rows remain ISS.
MF refinement: GO:0008047 enzyme activator activity -> GO:0001671 ATPase activator
activity and GO:0141109 transporter activator activity. Comparator: human PLN has
GO:0042030 ATPase inhibitor activity (IDA) and GO:0141110 transporter inhibitor activity
(IDA PMID:19708671); mouse Pln GO-CAM 62f58d8800005094 uses ATPase inhibitor activity.
DWORF is the mirror-image regulin, so the activator counterparts are the matched terms.
GO-CAM: no model in gocams/index.tsv contains STRIT1/P0DN84 (or mouse Dworf). Only a mouse
Pln model (62f58d8800005094) covers SERCA regulation.
No PAN-GO/IBA annotations (UniProt: "0 GO annotations based on evolutionary models").

Is DWORF protein present in human heart? The mouse antibody does not recognize human DWORF
PMID:35605666; human protein-level detection in tissue
is limited.