GGA proteins mediate the recycling pathway of memapsin 2 (BACE).
Memapsin 2 (BACE, beta-secretase) is a membrane-associated aspartic protease that initiates the hydrolysis of beta-amyloid precursor protein (APP) leading to the production of amyloid-beta (A beta) and the progression of Alzheimer disease. Both memapsin 2 and APP are transported from the cell surface to endosomes where APP is cleaved by memapsin 2. We described previously that the cytosolic domain of memapsin 2 contains an acid cluster-dileucine motif (ACDL) that binds the VHS (Vps-27, Hrs, and STAM) domain of Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins (He, X., Zhu, G., Koelsch, G., Rodgers, K. K., Zhang, X. C., and Tang, J. (2003) Biochemistry 42, 12174-12180). Here we report that GGA proteins colocalize in the trans-Golgi network and endosomes with memapsin 2 and a memapsin 2 chimera containing a cytosolic domain of a mannose-6-phosphate receptor. Depleting cellular GGA proteins with RNA interference or mutation of serine 498 to stop the phosphorylation of ACDL resulted in the accumulation of memapsin 2 in early endosomes. A similar change of memapsin 2 localization also was observed when a retromer subunit, VPS26, was depleted. These observations suggest that GGA proteins function with the phosphorylated ACDL in the memapsin 2-recycling pathway from endosomes to trans-Golgi on the way back to the cell surface.
He
Xiangyuan
X
Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, USA.
Li
Feng
F
Chang
Wan-Pin
WP
Tang
Jordan
J
D020727:ADP-Ribosylation Factors / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000502:physiology; D021601:trans-Golgi Network / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D034741:RNA, Small Interfering; C498296:VPS26A protein, human; D033921:Vesicular Transport Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D020727:ADP-Ribosylation Factors