KL (alpha-Klotho, Q9UEF7) curation notes

2026-09-30 Initial review (Claude Code)

Identity and architecture

• Type I single-pass membrane protein: signal peptide 1-33, extracellular 34-981, TM 982-1002,
  10-residue cytoplasmic tail [file:human/KL/KL-uniprot.txt "TOPO_DOM 1003..1012"].
• Two tandem GH1-like domains (KL1, KL2). UniProt: "the first region lacks the essential Glu active
  site residue at position 239, and the second one lacks the essential Glu active site residue at
  position 872" [file:human/KL/KL-uniprot.txt].
• Two transcripts: membrane form and a putative secreted KL1-only splice form
  PMID:9464267.
• Shed ectodomain circulates: PMID:15135068. The circulating species is 130 kDa (i.e. the shed full ectodomain), not the 70 kDa splice form
  PMID:15135068.

Core function: FGF23 co-receptor

• [PMID:17086194 "Klotho binds to FGF23"; "the concerted action of Klotho and FGFR1(IIIc) reconstitutes
  the FGF23 receptor"]; Klotho itself cannot signal ["Klotho alone seemed to be incapable of intracellular
  signalling"]. Abstract only.
• [PMID:16436388 "Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling
  activation by FGF23"; "FGF23 was pulled down with FGFR1c, -3c, and -4 only in the presence of Klotho"].
• Crystal structure of human FGF23-FGFR1c-alphaKlotho ectodomain ternary complex
  PMID:29342138. Soluble ectodomain is
  also a co-receptor ["demonstrating that αKlothoecto can serve as a bona fide co-receptor to support FGF23
  signaling in renal proximal tubules"].
• FGF19 also binds alphaKlotho in vitro PMID:18829467; FGF23 specificity lies in the FGF C-terminal tail.
• Human genetics: homozygous H193R causes hyperphosphatemic tumoral calcinosis PMID:17710231.

Enzymatic activity - weighed and rejected as core

• Tohyama 2004 (mouse KLFc fusion) reported weak beta-glucuronidase activity with 4-MU glucuronide and
  steroid glucuronides PMID:14701853. Abstract-only in cache.
• Chen 2018 (human ectodomain, full text) could not reproduce: PMID:29342138; both KL domains lack a
  catalytic Glu ["Moreover, both KL domains lack one of the key catalytic glutamates deep within the
  putative catalytic pocket."]; loop conformations "incompatible with an intrinsic glycosidase activity".
• Deep research (falcon) cites a 2020 structure-function study in which restoring the catalytic glutamates
  increased glucuronidase activity while reducing co-receptor activity; not independently verified here
  (no PMID cached), so not used as evidence.
• Decision: glucuronidase / O-glycosyl hydrolase MF terms MARK_AS_OVER_ANNOTATED (reported, contested,
  no physiological substrate); beta-glucosidase (TAS from 1997 homology statement) REMOVE; carbohydrate
  metabolic process REMOVE.

Rat-derived IEA process terms

• Rat Kl (Q9Z2Y9) source annotations: BP / norepinephrine from intracerebroventricular shRNA study
  PMID:20086041 - indirect, systemic. "response to X" terms come from rat IEP (expression) papers
  (PMID:22891896, PMID:20631679, PMID:17992255, PMID:11967236; not cached, identified via QuickGO).
• Decision: norepinephrine biosynthesis REMOVE (KL performs no step); BP MARK_AS_OVER_ANNOTATED;
  response to activity/angiotensin/vitamin D MARK_AS_OVER_ANNOTATED (expression responses);
  response to FGF KEEP_AS_NON_CORE (true by ancestry via FGFR signaling pathway).

Bone mineralization IMP (PMID:12110410)

• Association of a non-coding CA-repeat microsatellite with bone density in Japanese postmenopausal women
  PMID:12110410.
  Not a mutant phenotype; KL loss in humans causes ectopic calcification. MARK_AS_OVER_ANNOTATED.

NEW proposals and comparator checks

• GO:0015026 coreceptor activity: matches KLB review core MF; KL binds FGF23 and FGFR1c and cannot
  signal alone. Coreceptor is the best available MF; alternative would be FGF binding + FGFR binding only.
• GO:0055062 phosphate ion homeostasis: comparator check (QuickGO 2026-09-30): FGF23 (Q9GZV9) carries it
  (IMP PMID:11062477), FGFR1 and KLB do not. KL is the tissue-selective receptor component doing work in the
  FGF23 signal; human loss-of-function causes hyperphosphatemia. Proposed as NEW with IMP from
  PMID:17710231 but flagged in suggested_questions since FGFR1 lacks it.

Module relevance (fgfr_signaling)

• Coreceptor activity is a good fit for KL: it binds FGF23 with high affinity, binds FGFR1c, is required
  for receptor activation, lacks signaling capacity. Structural data call it a "scaffold"; the soluble
  ectodomain works in trans as well, so the module location (plasma membrane) captures the membrane form
  but the shed form is extracellular.