C-terminal domain of adaptor protein (AP) complexes medium mu subunits and its homologs (MHD); This family corresponds to the C-terminal domain of heterotetrameric AP complexes medium mu subunits and its homologs existing in monomeric stonins, delta-subunit of the heteroheptameric coat protein I (delta-COPI), a protein encoded by a pro-death gene referred as MuD (also known as MUDENG, mu-2 related death-inducing gene), an endocytic adaptor syp1, the mammalian FCH domain only proteins (FCHo1/2), SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1), and related proteins. AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. Stonins have been characterized as clathrin-dependent AP-2 mu chain related factors and may act as cargo-specific sorting adaptors in endocytosis. Coat protein complex I (COPI)-coated vesicles function in the early secretory pathway. They mediate the retrograde transport from the Golgi to the ER, and intra-Golgi transport. MuD is distantly related to the C-terminal domain of mu2 subunit of AP-2. It is able to induce cell death by itself and plays an important role in cell death in various tissues. Syp1 represents a novel type of endocytic adaptor protein that participates in endocytosis, promotes vesicle tabulation, and contributes to cell polarity and stress responses. It shares the same domain architecture with its two ubiquitously expressed mammalian counterparts, FCHo1/2, which represent key initial proteins ultimately controlling cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. They bind specifically to the plasma membrane and recruit the scaffold proteins eps15 and intersectin, which subsequently engage the adaptor complex AP2 and clathrin, leading to coated vesicle formation. Another mammalian neuronal-specific protein SGIP1 does have a C-terminal MHD and has been classified into this family as well. It is an endophilin-interacting protein that plays an obligatory role in the regulation of energy homeostasis. It is also involved in clathrin-mediated endocytosis by interacting with phospholipids and eps15.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 115532322   1 MSEESEGRPPIKVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGEYEMRM 57
Cdd:cd09258  214 ESEEKEGRPPISVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGDYQLRT 270

C-terminal domain of medium Mu1A subunit in ubiquitously expressed clathrin-associated adaptor protein (AP) complex AP-1; AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. There are four AP complexes, AP-1, AP-2, AP-3, and AP-4, described in various eukaryotic organisms. Each AP complex consists of four subunits: two large chains (one each of gamma/alpha/delta/epsilon and beta1-4, respectively), a medium mu chain (mu1-4), and a small sigma chain (sigma1-4). Each of the four subunits from the different AP complexes exhibits similarity with each other. This subfamily corresponds to the C-terminal domain of heterotetrameric clathrin-associated adaptor protein complex 1 (AP-1) medium mu1A subunit encoded by ap1m1 gene, which is ubiquitously expressed in all mammalian tissues and cells. AP-1 has been implicated in bidirectional transport between the trans-Golgi network (TGN) and endosomes. It is involved in the formation of clathrin-coated vesicles (CCVs) from the trans-Golgi network (TGN). The ubiquitous AP-1 is recruited to the TGN membrane, as well as to immature secretory granules. Recruitment of AP-1 to the TGN membrane is regulated by a small GTPase, ADP-ribosylation factor 1 (ARF1). Phosphorylation/dephosphorylation events can also regulate the function of AP-1. The membrane-anchored cargo molecules can be linked to the outer lattice of CCVs by AP-1. Those cargo molecules interact with adaptors through short sorting signals in their cytosolic segments. Tyrosine-based endocytotic signals are one of the most important sorting signals. They are of the form Y-X-X-Phi, where Y is tyrosine, X is any amino acid and Phi is a bulky hydrophobic residue that can be Leu, Ile, Met, Phe, or Val. These kinds of sorting signals can be recognized by the C-terminal domain of AP-1 mu1A subunit, also known as Y-X-X-Phi signal-binding domain that contains two hydrophobic pockets, one for the tyrosine-binding and one for the bulky hydrophobic residue-binding.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 115532322   1 MSEESEGRPPIKVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGEYEMRM 57
Cdd:cd09258  214 ESEEKEGRPPISVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGDYQLRT 270

C-terminal domain of medium Mu1A subunit in ubiquitously expressed clathrin-associated adaptor protein (AP) complex AP-1; AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. There are four AP complexes, AP-1, AP-2, AP-3, and AP-4, described in various eukaryotic organisms. Each AP complex consists of four subunits: two large chains (one each of gamma/alpha/delta/epsilon and beta1-4, respectively), a medium mu chain (mu1-4), and a small sigma chain (sigma1-4). Each of the four subunits from the different AP complexes exhibits similarity with each other. This subfamily corresponds to the C-terminal domain of heterotetrameric clathrin-associated adaptor protein complex 1 (AP-1) medium mu1A subunit encoded by ap1m1 gene, which is ubiquitously expressed in all mammalian tissues and cells. AP-1 has been implicated in bidirectional transport between the trans-Golgi network (TGN) and endosomes. It is involved in the formation of clathrin-coated vesicles (CCVs) from the trans-Golgi network (TGN). The ubiquitous AP-1 is recruited to the TGN membrane, as well as to immature secretory granules. Recruitment of AP-1 to the TGN membrane is regulated by a small GTPase, ADP-ribosylation factor 1 (ARF1). Phosphorylation/dephosphorylation events can also regulate the function of AP-1. The membrane-anchored cargo molecules can be linked to the outer lattice of CCVs by AP-1. Those cargo molecules interact with adaptors through short sorting signals in their cytosolic segments. Tyrosine-based endocytotic signals are one of the most important sorting signals. They are of the form Y-X-X-Phi, where Y is tyrosine, X is any amino acid and Phi is a bulky hydrophobic residue that can be Leu, Ile, Met, Phe, or Val. These kinds of sorting signals can be recognized by the C-terminal domain of AP-1 mu1A subunit, also known as Y-X-X-Phi signal-binding domain that contains two hydrophobic pockets, one for the tyrosine-binding and one for the bulky hydrophobic residue-binding.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 115532322   1 MSEESEGRPPIKVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGEYEMRM 57
Cdd:cd09258  214 ESEEKEGRPPISVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGDYQLRT 270

C-terminal domain of medium Mu1B subunit in epithelial cell-specific clathrin-associated adaptor protein (AP) complex AP-1; AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. There are four AP complexes, AP-1, AP-2, AP-3, and AP-4, described in various eukaryotic organisms. Each AP complex consists of four subunits: two large chains (one each of gamma/alpha/delta/epsilon and beta1-4, respectively), a medium mu chain (mu1-4), and a small sigma chain (sigma1-4). Each of the four subunits from different AP complexes exhibits similarity with each other. This subfamily corresponds to the C-terminal domain of heterotetrameric clathrin-associated adaptor protein complex 1 (AP-1) medium mu1B subunit encoded by ap1m2 gene exclusively expressed in polarized epithelial cells. Epithelial cell-specific AP-1 is used to sort proteins to the basolateral plasma membrane, which involves the formation of clathrin-coated vesicles (CCVs) from the trans-Golgi network (TGN). Recruitment of AP-1 to the TGN membrane is regulated by a small GTPase, ADP-ribosylation factor 1 (ARF1). The phosphorylation/dephosphorylation events can also regulate the function of AP-1. The membrane-anchored cargo molecules can be linked to the outer lattice of CCVs by AP-1. Those cargo molecules interact with adaptors through short sorting signals in their cytosolic segments. Tyrosine-based endocytotic signals are one of the most important sorting signals. They are of the form Y-X-X-Phi, where Y is tyrosine, X is any amino acid and Phi is a bulky hydrophobic residue that can be Leu, Ile, Met, Phe, or Val. These kinds of sorting signals can be recognized by the C-terminal domain of AP-1 mu1B subunit, also known as Y-X-X-Phi signal-binding domain that contains two hydrophobic pockets, one for the tyrosine-binding and one for the bulky hydrophobic reside-binding. Besides, AP-1 mu1B subunit mediates the basolateral recycling of low-density lipoprotein receptor (LDLR) and transferrin receptor (TfR) from the sorting endosomes, where the basolateral sorting signal does not belong to the tyrosine-based signals. Thus, the binding site in mu1B subunit of AP-1 for the signals of LDLR and TfR might be distinct from that for YXXPhi signals.

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                 ....*....|....*....|....*....|....*....|....*....|....
gi 115532322   3 EESEGRPPIKVKFEIPYFTTSGIQVRYLKIIEKSGYQALPWVRYITQNGEYEMR 56
Cdd:cd09259  215 EELEGKPPITVKFEIPYFTVSGIQVRYMKIIEKSGYQALPWVRYITQSGDYQLR 268

C-terminal domain of adaptor protein (AP) complexes medium mu subunits and its homologs (MHD); This family corresponds to the C-terminal domain of heterotetrameric AP complexes medium mu subunits and its homologs existing in monomeric stonins, delta-subunit of the heteroheptameric coat protein I (delta-COPI), a protein encoded by a pro-death gene referred as MuD (also known as MUDENG, mu-2 related death-inducing gene), an endocytic adaptor syp1, the mammalian FCH domain only proteins (FCHo1/2), SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1), and related proteins. AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. Stonins have been characterized as clathrin-dependent AP-2 mu chain related factors and may act as cargo-specific sorting adaptors in endocytosis. Coat protein complex I (COPI)-coated vesicles function in the early secretory pathway. They mediate the retrograde transport from the Golgi to the ER, and intra-Golgi transport. MuD is distantly related to the C-terminal domain of mu2 subunit of AP-2. It is able to induce cell death by itself and plays an important role in cell death in various tissues. Syp1 represents a novel type of endocytic adaptor protein that participates in endocytosis, promotes vesicle tabulation, and contributes to cell polarity and stress responses. It shares the same domain architecture with its two ubiquitously expressed mammalian counterparts, FCHo1/2, which represent key initial proteins ultimately controlling cellular nutrient uptake, receptor regulation, and synaptic vesicle retrieval. They bind specifically to the plasma membrane and recruit the scaffold proteins eps15 and intersectin, which subsequently engage the adaptor complex AP2 and clathrin, leading to coated vesicle formation. Another mammalian neuronal-specific protein SGIP1 does have a C-terminal MHD and has been classified into this family as well. It is an endophilin-interacting protein that plays an obligatory role in the regulation of energy homeostasis. It is also involved in clathrin-mediated endocytosis by interacting with phospholipids and eps15.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 115532322   3 EESEGRPPIKVKFEIPYFTTSGIQVRYLKIIEKS--GYQALPWVRYITQNGEYEMR 56
Cdd:cd07954  190 ECPEEAPPVSVSFEIPETTGSGIQVRSLQVFDEKnpGHDPIKWVRYITHTGKYVAR 245

C-terminal domain of medium Mu4 subunit in adaptor protein (AP) complex AP-4; AP complexes participate in the formation of intracellular coated transport vesicles and select cargo molecules for incorporation into the coated vesicles in the late secretory and endocytic pathways. There are four AP complexes, AP-1, AP-2, AP-3, and AP-4, described in various eukaryotic organisms. Each AP complex consists of four subunits: two large chains (one each of gamma/alpha/delta/epsilon and beta1-4, respectively), a medium mu chain (mu1-4), and a small sigma chain (sigma1-4). Each of the four subunits from the different AP complexes exhibits similarity with each other. This family corresponds to the C-terminal domain of heterotetrameric adaptor protein complex 4 (AP-4) medium mu4 subunit. AP-4 plays a role in signal-mediated trafficking of integral membrane proteins in mammalian cells. Unlike other AP complexes, AP-4 is found only in mammals and plants. It is believed to be part of a nonclathrin coat, since it might function independently of clathrin, a scaffolding protein participating in the formation of coated vesicles. Recruitment of AP-4 to the trans-Golgi network (TGN) membrane is regulated by a small GTPase, ADP-ribosylation factor 1 (ARF1) or a related protein. Membrane-anchored cargo molecules interact with adaptors through short sorting signals in their cytosolic segments. One of the most important sorting signals binding to mu subunits of AP complexes are tyrosine-based endocytotic signals, which are of the form Y-X-X-Phi, where Y is tyrosine, X is any amino acid and Phi is a bulky hydrophobic residue that can be Leu, Ile, Met, Phe, or Val. However, AP-4 does not bind most canonical tyrosine-based signals except for two naturally occurring ones from the lysosomal membrane proteins CD63 and LAMP-2a. It binds YX [FYL][FL]E motif, where X can be any residue, from the cytosolic tails of amyloid precursor protein (APP) family members in a distinct way.

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gi 115532322  10 PIKVKFEIPYFTTSGIQVRYLKIIEK-SGYQALPWVRYITQNGEYEMRM 57
Cdd:cd09253  223 PISLSFEIPMYNVSGLQVRYLRILERsSSYNPHRWVRYVTQSSSYVCRI 271