AP4 binds APP

Stable Identifier
Reaction [binding]
Homo sapiens
AP4 complex binds APP, targeting it to lysosomes
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The family of heterotetrameric adaptor protein (AP) complexes function as vesicle coat components, involved in targeting cargo proteins from post-Golgi compartments to the endosomal-lysosomal system. Adaptor protein 4 (AP4) is the most recently discovered and least characterised member of this family. AP4 consists of four subunits; two large adaptins (AP4E1 and AP4B1), a medium adaptin (AP4M1) and a small adaptin (AP4S1). The medium (mu) adaptins of all AP complexes can recognise and interact with tyrosine-based (YXXphi) sorting signals found within the cytoplasmic tails of integral membrane proteins (Aguilar et al. 2001, Hirst et al. 1999). The amyloid precursor protein (APP), implicated in Alzheimer's disease, contains such a signal in its cytoplasmic tail. It can therefore bind to AP4M1 of the AP4 complex and subsequently, be transported from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein. Disruption of the this interaction decreases localisation of APP to endosomes and enhances gamma-secretase-catalysed cleavage of APP to the pathogenic amyloid-beta peptide (Burgos et al. 2010).

Defects in AP4M1 can cause cerebral palsy, spastic quadriplegic 3 (CPSQ3; MIM:612936), a non-progressive disorder of movement and/or posture resulting from defects in CNS development (Verkerk et al. 2009). Defects in AP4S1 can cause cerebral palsy, spastic quadriplegic 6 (CPSQ6; MIM:614067), a neurodevelopmental disorder characterised by hypertonia and spasticity, and severe mental retardation with poor or absent speech development (Abou Jamra et al. 2011).
Literature References
PubMed ID Title Journal Year
21620353 Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature

Munnich, A, Abou Jamra, R, Philippe, O, Nöthen, MM, Colleaux, L, Raas-Rothschild, A, Brockschmidt, FF, Borck, G, Ekici, A, Graf, E, Buchert, R, Reis, A, Eck, SH, Strom, TM

Am. J. Hum. Genet. 2011
10436028 Characterization of a fourth adaptor-related protein complex

Hirst, J, Bright, NA, Rous, B, Robinson, MS

Mol. Biol. Cell 1999
20230749 Sorting of the Alzheimer's disease amyloid precursor protein mediated by the AP-4 complex

Prabhu, Y, Hurley, JH, Mardones, GA, Burgos, PV, Rojas, AL, Bonifacino, JS, daSilva, LL

Dev. Cell 2010
11139587 Signal-binding specificity of the mu4 subunit of the adaptor protein complex AP-4

Aguilar, RC, Ohno, H, Bonifacino, JS, Boehm, M, Saito, T, Tomita, K, Gorshkova, I, Crouch, RJ

J. Biol. Chem. 2001
19559397 Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy

Swagemakers, S, Dumee, B, Catsman-Berrevoets, C, Willems, PJ, Mancini, GM, van der Spek, PJ, Wessels, MW, Lequin, MH, Kros, JM, Willemsen, R, Bertoli-Avella, AM, van Zwol, AL, Govaert, P, Hirst, J, Schot, R, Schellekens, K, Verheijen, FW, de Graaff, E, Verkerk, AJ, Dudink, J, de Coo, IF

Am. J. Hum. Genet. 2009
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