Journal of research done while reviewing the GOA annotations. Provenance is given inline
as [PMID:NNNN "verbatim quote"] or [file:...] where a quote comes from a cached
publication or the deep-research report.
Unconventional myosin-VIIa, HGNC:7606, disease alias USH1B. Domain layout: N-terminal
motor domain, neck with five IQ motifs, a single-alpha-helix (SAH) lever-arm extension,
then a long tail of two MyTH4-FERM modules separated by an SH3 domain.
The InterPro FERM/Band-4.1 signatures on this entry therefore describe the cargo-binding
tail, not an acyl-CoA-binding enzyme — worth noting because the deep-research prompt
listed only FERM domains.
Heissler & Manstein characterised the isolated human motor domain fused to an artificial
lever arm. The key facts for annotation are a rate-limiting ADP release step, high duty
ratio, and high F-actin affinity:
Free Mg2+ in the physiological range switches the motor between cargo-moving and
tension-bearing modes. This is the biochemical basis for treating MYO7A as a
tension-holding motor rather than a fast transporter, and it justifies ACCEPTing
GO:0000146, GO:0051015, GO:0005524 and GO:0030048 as core.
Caveat recorded in the reference review: the construct is a motor domain plus artificial
lever arm, so these numbers describe the motor module, not the autoinhibited full-length
molecule. Full-length human MYO7A is monomeric and folded until cargo adaptors open it
(Holló et al. 2023, JBC 299:105243, via the deep-research report; not separately cached).
The functionally decisive site is the UTLD of mature stereocilia, not the base:
The tripartite MYO7A–sans(USH1G)–harmonin-b(USH1C) complex was demonstrated by
co-transfection in COS7 cells; the hair-cell localisation is rodent. Hence the new
GO:1990435 annotation was entered as ISS rather than IDA for the human protein.
This is a tension-bearing complex of the mature bundle — deliberately distinguished in
the review from the transient ankle-link/USH2 complex of developing bundles.
UniProt states the same network at the level of function:
"Motor protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and
MYO7A that mediates mechanotransduction in cochlear hair cells."
(MYO7A-uniprot.txt, FUNCTION block, ECO:0000269|PubMed:21709241.)
MYRIP is the RAB27A effector that couples melanosomes to the motor:
Human loss-of-function evidence for the melanosome role (basis for the NEW GO:0032400
annotation, IMP):
Note the direction of the effect: the motor constrains long-range (microtubule-driven)
movement, i.e. it captures and retains melanosomes on apical cortical actin. That is why
GO:0032400 melanosome localization was preferred over GO:0032402 melanosome transport.
Lysosomes:
The same paper summarises the phagosome literature: myosin-VIIa is not needed for ROS
binding or ingestion, only for later steps —
PMID:16001398 and
PMID:16001398.
This is the reason GO:0007040 lysosome organization was MODIFYed to GO:0032418 lysosome
localization on both the IDA and the ARBA IEA: the demonstrated activity is positioning
of the organelle, not biogenesis.
PMID:8842737
(pigment epithelium and photoreceptors) — and crucially the species difference that
explains why shaker-1 mice have no retinal phenotype:
PMID:8842737.
Sub-cellular distribution in human photoreceptors:
PMID:8842737
Opsin transport and the spectrin betaV scaffold:
PMID:23704327
PMID:23704327
Both of the vague "intracellular protein localization" (GO:0008104) annotations — the
Ensembl IEA and the curator ISS, both from mouse P97479 — were MODIFYed to GO:0036372
opsin transport on this basis.
GO:0042462 eye photoreceptor cell development (IC). The IC is drawn from
GO:0001917 (inner segment localisation). Presence of a protein in a developing cell does
not establish a developmental role, and the paper's own interpretation is about renewal
and trafficking:
PMID:8842737. USH1B retinopathy is progressive and post-developmental. MODIFY →
GO:0045494 photoreceptor cell maintenance.
PMID:11398101 cited for two MYO7A IMP annotations. Full text is cached and is
entirely an experimental study of PCDH15/USH1F; MYO7A appears only as background:
PMID:11398101. The claims (hearing, light perception) are
correct and independently supported by PMID:7870171, so both annotations were ACCEPTed
rather than removed, per the "do not overrule curators" rule, and the citation problem
was recorded in reference_review as MISCITED / LOW relevance instead.
Bare GO:0005515 protein binding (×2, CIB2 and MYRIP) → MARK_AS_OVER_ANNOTATED.
Both interactions are real and well demonstrated, but the term carries no functional
information. Interesting detail for the CIB2 one: MYO7A is not required for CIB2
targeting — PMID:23023331 — so this is not a recruitment relationship.
GO:0019904 protein domain specific binding → MARK_AS_OVER_ANNOTATED for the same
reason (uninformative binding term).
GO:0048666 neuron development (ARBA) → MARK_AS_OVER_ANNOTATED. Hair cells are
mechanosensory epithelial cells, not neurons; the photoreceptor role is maintenance and
transport in a differentiated cell. Not strictly false (photoreceptors are neurons) but
a large over-generalisation from an unsupervised rule.
GO:0005829 cytosol. Both the ARBA IEA and the IDA (PMID:15300860) were set to
KEEP_AS_NON_CORE for consistency. The IDA comes from a study that expressed MYO7A IQ5
peptides in smooth muscle cells of microarteries — a heterologous system — and full text
is not cached, so the curator's call is not challenged; but cytosol is not a functional
site for this motor.
GO:0120044 stereocilium base (IEA + ISS) → KEEP_AS_NON_CORE. Myosin-VIIa is
distributed along stereocilia including the basal/ankle-link region of developing
bundles, so the mouse-derived annotation stands; but the decisive site in the mature
bundle is the UTLD, which is why GO:1990435 was added rather than substituted.
IBA block. No IBA was challenged. Two points followed the project's IBA guidance:
MYO7A appearing in its own WITH/FROM for GO:0000146, GO:0030048 and GO:0007605 is
expected (its own experimental annotation seeded the IBD) and is not circular; and the
short donor list for GO:0007423 (FBgn0000317 crinkled, MGI:104510 Myo7a, PTN000321046)
is not weak evidence.
GO:0005516 calmodulin binding accepted as core: the IQ-bound light chains are the lever
arm, and Ca2+-dependent CaM dissociation is how the motor is switched off. UniProt also
records CALML4 as a Ca2+-insensitive light chain (PubMed:32209652), which may preserve
lever-arm integrity when Ca2+ rises.