Aph1a (rat) - manual literature research

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Identity

• UniProt A0ABK0KYA7 (TrEMBL, unreviewed), rat Aph1a, RGD:1311546, GeneID 365872; 265 aa,
  seven predicted TM helices; Pfam PF06105 Aph-1; PANTHER PTHR12889. Ortholog of human
  APH1A (Q96BI3, isoform L 265 aa) and mouse Aph1a (Q8BVF7).
• Conserved intramembrane His-171 and His-197 are present in the rat sequence (checked
  against the UniProt SQ block).

Function (gamma-secretase subunit)

• Gamma-secretase is "a ubiquitous, multiprotein enzyme composed of presenilin, nicastrin,
  Aph-1, and Pen-2. It mediates the intramembrane proteolysis of many type 1 proteins"
  PMID:20145246. Presenilin is the catalytic aspartyl protease; Aph-1 is non-catalytic.
• Aph-1 is thought to "initiate complex assembly in the endoplasmic reticulum" by binding
  nicastrin early in assembly PMID:20145246.
• Aph-1 associates with full-length and C-terminal fragments of substrates (APP, Jagged);
  endogenous rat Aph-1 co-immunoprecipitated with endogenous Jagged-1 from E13 rat embryo
  microsomes; His-171/His-197 needed for efficient substrate binding and activity
  PMID:20145246.
• Mouse genetics: "Aph1A-/- embryos show a lethal phenotype characterized by angiogenesis
  defects in the yolk sac, neuronal tube malformations, and mild somitogenesis defects"
  while Aph1B/C null mice survive [PMID:15665098, abstract only].
• APH-1 is S-palmitoylated (Cys182, Cys245) which affects stability and raft association
  but not processing [PMID:19028695, abstract only].

Localization in rat brain

• Aph-1aL co-fractionates with other gamma-secretase components in an endosome/plasma
  membrane-enriched iodixanol fraction, in synaptic membranes and in crude and CPG-purified
  synaptic vesicles; active gamma-secretase (biotinylated inhibitor) co-localizes partially
  with Rab5 and with presynaptic synapsin PMID:20126630.