trans-Golgi network membrane
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).