Characterization of basolateral-targeting signals in the neonatal Fc receptor.
The neonatal Fc receptor, FcRn, transports proteins through cells, avoiding degradative compartments. FcRn is used in many physiological processes where proteins must remain intact while they move through cells. These contexts include the transport of IgG antibodies from mother to offspring, and the protection of IgG and albumin from catabolism. In polarized cell models, FcRn in the plasma membrane is predominantly at the basolateral surface. This distribution depends on two signals that overlap endocytosis signals. One of these signals resembles a YXXPhi motif, but with a tryptophan in place of the critical tyrosine residue; the other is a DDXXXLL signal. We examined the effects of mutations in and around these signals on the basolateral targeting of rat FcRn in rat inner medullary collecting duct cells. We also studied a second acidic cluster, Glu331/Glu333, some distance from either endocytosis signal. Some amino acid substitutions in the W-2 and W+3 positions disrupted the tryptophan-based basolateral-targeting signal without impairing its function in endocytosis. The tryptophan-based basolateral targeting and endocytosis signals are thus distinct but overlapping, as has been seen for collinear tyrosine-based signals. Surprisingly, the tryptophan-based basolateral-targeting signal required the aspartate pair of the dileucine-based signal. This acidic cluster, separated by two amino acids from the Phi residue of the tryptophan signal, is therefore a component of both of the basolateral-targeting signals. The acidic cluster Glu-331/Glu333 was not required for basolateral targeting, but its replacement reduced endocytosis.
Newton
Estelle E
EE
Rosenstiel Center for Basic Biomedical Sciences and Biology Department, Brandeis University, Waltham, MA 02254-9110, USA.
Wu
Zhen
Z
Simister
Neil E
NE
D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D002460:Cell Line; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D007112:Immunity, Maternally-Acquired / Q000502:physiology; D007074:Immunoglobulin G / Q000378:metabolism*; D007679:Kidney Medulla / Q000166:cytology / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D051381:Rats; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal