This 4TMS protein superfamily includes CD81 (TAPA-1; tetraspannin-28), a co-receptor of hepatitis C virus (HCV) in a heterodimer with SR-B1 (TC#9.B.39.1.3) (Cocquerel et al. 2003) as well as CD151 (Tetraspannin-24). Loss yields poor B-cell development and antibody deficiency (van Zelm et al. 2010). This protein functions in signal transmission. Defects are the cause of immunodeficiency common variable type 6 (CVID6) and prevent efficient antibody secretion. Tetraspanins regulate the trafficking and function of partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system (Charrin et al. 2014). Sperm-egg interaction and fusion would not happen in mammals without the interaction of tetraspanin superfamily members including protein CD81 (Jankovicova et al. 2016).

Tetraspanins may be involved in cell proliferation and motility. Defects of TSPAN7 in humans result in mental retardation, called x-linked type 58 (MRX58) (Hemler 2005). Orthologues of several human tetraspanins have been studied in other organisms (Yeh and Klesius 2012). One such protein, CD63, is involved in trafficking and transport regulation (Pols and Klumperman 2009). In addition (Susa et al. 2023):

Tetraspanins regulate signal transduction by interacting with partner proteins belonging to different protein families, including extracellular enzymes, integrins, members of the immunoglobulin superfamily, and intracellular signaling proteins.
Structures of full-length tetraspanins have revealed a common overall architecture, with a cone-shaped transmembrane (TM) domain containing an intramembrane binding pocket. This pocket can bind lipids, which appear to modulate tetraspanin function.
Many tetraspanins are conformationally dynamic, existing in at least two states with distinct TM conformations and ectodomain orientations.
The molecular association of a tetraspanin with its partner can be mediated through the large extracellular loop (EC2 domain) and/or the TM domain. The dependency for each region differs based on the bound partner (Susa et al. 2023).

TSPAN-13 specifically modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel and accelerates the voltage-dependent activation and inactivation of Ba²⁺ currents through Cav2.2 (TC# 1.A.1.11.9). It may regulate Cav2.2 Ca²⁺ channel activity in defined synaptic membrane compartments and thereby influence transmitter release (Mallmann et al. 2013).

Disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions of over 40 different transmembrane target proteins, including Notch and amyloid precursor protein in humans (Haining et al. 2012). ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which comprise a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane ''partner'' proteins (Noy et al. 2016). This is achieved by specific tetraspanin-partner interactions. ADAM10 interacts with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the TspanC8 subgroup of tetraspanins, all six of which promote ADAM10 maturation (Jouannet et al. 2016). Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. TspanC8 tetraspanins are thus essential regulators of ADAM10 maturation and trafficking to the cell surface (Matthews et al. 2016). The biology of tetraspanins and how they interact with APP processing pathways have been reviewed (Seipold and Saftig 2016).

There are 33 mammalian tetraspanins, most of which interact with and regulate specific partner proteins within membrane nanodomains, some of which are described above. Tetraspanins appear to have a cone-shaped structure with a cholesterol-binding cavity, which may enable tetraspanins to undergo cholesterol-regulated conformational changes. The TspanC8 subgroup of tetraspanins, including Tspan5, 10, 14, 15, 17 and 33, regulate Adam10. Thus, TspanC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation. Different TspanC8s localise ADAM10 to different subcellular localisations and may cause ADAM10 to adopt distinct conformations with cleavage of distinct substrates. Matthews et al. 2017 proposed that ADAM10 should be regarded as six different scissor proteins depending on its interacting TspanC8.

β-cell TSPAN-7 regulates Ca²⁺ handling and hormone secretion. Dickerson et al. 2020 found that TSPAN-7 reduces beta-cell glucose-stimulated Ca²⁺ entry, slows Ca²⁺ oscillation frequency, and decreases glucose-stimulated insulin secretion. TSPAN-7 controls β-cell function through a direct interaction with L-type voltage-dependent Ca²⁺ channels (CaV 1.2 and CaV 1.3), which reduces channel Ca²⁺ conductance. TSPAN-7 slows activation of CaV 1.2 and accelerates recovery from voltage-dependent inactivation; TSPAN-7 also slows CaV 1.3 inactivation kinetics. These findings strongly implicate TSPAN-7 as a key regulator in determining the setpoint of glucose-stimulated Ca(2+) influx and insulin secretion (Dickerson et al. 2020).

8.A.40 The Tetraspanin (Tetraspanin) Family This 4TMS protein superfamily includes CD81 (TAPA-1; tetraspannin-28), a co-receptor of hepatitis C virus (HCV) in a heterodimer with SR-B1 (TC#9.B.39.1.3) (Cocquerel et al. 2003) as well as CD151 (Tetraspannin-24). Loss yields poor B-cell development and antibody deficiency (van Zelm et al. 2010). This protein functions in signal transmission. Defects are the cause of immunodeficiency common variable type 6 (CVID6) and prevent efficient antibody secretion. Tetraspanins regulate the trafficking and function of partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system (Charrin et al. 2014). Sperm-egg interaction and fusion would not happen in mammals without the interaction of tetraspanin superfamily members including protein CD81 (Jankovicova et al. 2016). Tetraspanins may be involved in cell proliferation and motility. Defects of TSPAN7 in humans result in mental retardation, called x-linked type 58 (MRX58) (Hemler 2005). Orthologues of several human tetraspanins have been studied in other organisms (Yeh and Klesius 2012). One such protein, CD63, is involved in trafficking and transport regulation (Pols and Klumperman 2009). In addition (Susa et al. 2023): Tetraspanins regulate signal transduction by interacting with partner proteins belonging to different protein families, including extracellular enzymes, integrins, members of the immunoglobulin superfamily, and intracellular signaling proteins. Structures of full-length tetraspanins have revealed a common overall architecture, with a cone-shaped transmembrane (TM) domain containing an intramembrane binding pocket. This pocket can bind lipids, which appear to modulate tetraspanin function. Many tetraspanins are conformationally dynamic, existing in at least two states with distinct TM conformations and ectodomain orientations. The molecular association of a tetraspanin with its partner can be mediated through the large extracellular loop (EC2 domain) and/or the TM domain. The dependency for each region differs based on the bound partner (Susa et al. 2023). TSPAN-13 specifically modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel and accelerates the voltage-dependent activation and inactivation of Ba²⁺ currents through Cav2.2 (TC# 1.A.1.11.9). It may regulate Cav2.2 Ca²⁺ channel activity in defined synaptic membrane compartments and thereby influence transmitter release (Mallmann et al. 2013). Disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions of over 40 different transmembrane target proteins, including Notch and amyloid precursor protein in humans (Haining et al. 2012). ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which comprise a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane ''partner'' proteins (Noy et al. 2016). This is achieved by specific tetraspanin-partner interactions. ADAM10 interacts with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the TspanC8 subgroup of tetraspanins, all six of which promote ADAM10 maturation (Jouannet et al. 2016). Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. TspanC8 tetraspanins are thus essential regulators of ADAM10 maturation and trafficking to the cell surface (Matthews et al. 2016). The biology of tetraspanins and how they interact with APP processing pathways have been reviewed (Seipold and Saftig 2016). There are 33 mammalian tetraspanins, most of which interact with and regulate specific partner proteins within membrane nanodomains, some of which are described above. Tetraspanins appear to have a cone-shaped structure with a cholesterol-binding cavity, which may enable tetraspanins to undergo cholesterol-regulated conformational changes. The TspanC8 subgroup of tetraspanins, including Tspan5, 10, 14, 15, 17 and 33, regulate Adam10. Thus, TspanC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation. Different TspanC8s localise ADAM10 to different subcellular localisations and may cause ADAM10 to adopt distinct conformations with cleavage of distinct substrates. Matthews et al. 2017 proposed that ADAM10 should be regarded as six different scissor proteins depending on its interacting TspanC8. β-cell TSPAN-7 regulates Ca²⁺ handling and hormone secretion. Dickerson et al. 2020 found that TSPAN-7 reduces beta-cell glucose-stimulated Ca²⁺ entry, slows Ca²⁺ oscillation frequency, and decreases glucose-stimulated insulin secretion. TSPAN-7 controls β-cell function through a direct interaction with L-type voltage-dependent Ca²⁺ channels (CaV 1.2 and CaV 1.3), which reduces channel Ca²⁺ conductance. TSPAN-7 slows activation of CaV 1.2 and accelerates recovery from voltage-dependent inactivation; TSPAN-7 also slows CaV 1.3 inactivation kinetics. These findings strongly implicate TSPAN-7 as a key regulator in determining the setpoint of glucose-stimulated Ca(2+) influx and insulin secretion (Dickerson et al. 2020).
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Examples:
TC#	Name	Organismal Type	Example
8.A.40.1.1	CD81 (TAPA1, Tspan28) co-receptor of Hepatitis C Virus (HCV); 236 aas; it forms a heterodimer with SR-B1 (TC#9.B.39.1.3). Defects cause CVID6. It plays a role in hepatitis C entry via endocytosis (Farquhar et al., 2011), and also plays roles in immune and other physiological functions (Yeh and Klesius 2009). Sperm-egg interaction and fusion would not happen in mammals without tetraspanin superfamily members including protein CD81 (Jankovicova et al. 2016). Abnormal levels occur in plasma neuron-derived extracellular vesicles of early schizophrenia and other neurodevelopmental diseases (Goetzl et al. 2022). Tetraspanin CD81 serves as a functional entry factor for porcine circovirus type 2 infection (Li et al. 2025).	Animals	*CD81 of Homo sapiens* (P60033)**

8.A.40.1.10	*Tetraspanin 10 (Haining et al., 2012).*	Animals	Tetraspanin 10 of Homo sapiens

8.A.40.1.11	*Tetraspanin 33; penumbra (Haining et al.* 2012).**	Animals	Penumbra of Homo sapiens

8.A.40.1.12	Catfish CD63 antigen tetraspanin of 237 aas (Yeh and Klesius 2010). Involved in trafficking and transport regulation (Pols and Klumperman 2009).	Animals	*CD63 of Ictalurus punctatus* (Channel catfish) (Silurus punctatus)**

8.A.40.1.13	Uncharacterized protein of 221 aas and 4 TMSs.	Animals (insects)	UP of Danaus plexippus

8.A.40.1.14	Uncharacterized protein of 219 aas and 4 TMSs.	Algae	UP of Galdieria sulphuraria

8.A.40.1.15	The tetraspan 24 protein, TSPAN24 or CD151 of 254 aas and 4 TMSs in a 3 + 1 TM arrangement. It is essential for the proper assembly of the glomerular and tubular basement membranes in kidney, and also functions in egg-sperm interactions, possibly in cell-cell fusion, where oocyte CD151 interacts with CD49 in the sperm (Sabetian et al. 2014).	Animals	CD151 of Homo sapiens

8.A.40.1.16	*Tetraspanin-3 (TSPAN3) of 253 aas and 4 TMSs in a 3+ 1 arrangement. Plays a role in myeloid leukemia and other cancers (Yang et al.* 2016).**		TSPAN3 of Homo sapiens

8.A.40.1.17	*Tetraspannin 15, TSPAN15 of 294 aas and 4 TMSs. Interacts with and regulates the targetting and activity of the sheddase, ADAM10 (TC# 8.A.77) (Prox et al.* 2012).**		TSPAN15 of Homo sapiens

8.A.40.1.18	Human Leukocyte surface antigen CD53 of 219 aas and 4 TMSs (Halova and Draber 2016). CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes (Higgins et al. 2022).		CD53 of Homo sapiens

8.A.40.1.19	Antigen CD63 of 238 aas and 4 TMSs. It functions as cell surface receptor, and plays a role in the activation of cellular signaling cascades. It also plays a role in intracellular and extracellular vesicular transport processes, and is required for normal trafficking that is essential for the development and maturation of melanocytes (van Niel et al. 2011; Lee et al. 2014). CD63 is on natural exosomes (cell derived extracellular vesicles), and it is highly enriched on the external surfaces of these membranes (Curley et al. 2020). Distinct scaffolds based on engineering of CD63 enable flexible engineering of the exosome surface for applications in disease-targeted drug delivery and therapy. CD63 proximal interacting proteins comprise the network of partners required for endocytic trafficking and extracellular vesicle cargo sorting, formation, and secretion (Cheerathodi et al. 2021). Climbazole and heparin undermine membrane-bound tetraspanin CD63 expression, significantly disrupted ALIX protein, and alter human carcinoma lung cell-derived extracellular vesicle formation (Ipinmoroti et al. 2023). CD63 also participates in extracellular vesicle loading and delivery (Bui et al. 2023); see also TC Family 1.F.4.		CD63 of Homo sapiens

8.A.40.1.2	Tetraspanin-7 (Tspan-7; TALLA1; MXS1; TM4SF2) (Hemler, 2005). Defects in humans result in mental retardation, called x-linked type 58 (MRX58) (Hemler, 2005). Contains sphingolipid binding motifs (Björkholm et al. 2014). Tspan-7 is the target of autoantibodies and type I diabetes (McLaughlin et al. 2016). Tspan7 is an islet autoantigen involved in autoimmune type 1 diabetes and regulates beta-cell L-type Ca²⁺ channel activity (McLaughlin et al. 2022). It thereby regulates Ca²⁺-dependent exocytosis in beta-cells (McLaughlin et al. 2022).	Animals	*Tspan-7 of Homo sapiens* (P41732)**

8.A.40.1.20	Tetraspanin-12, Tspan12, of 305 aas and 4 TMSs. Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to accumulation of beta-catenin (CTNNB1) and stimulation of LEF/TCF-mediated transcriptional programs (Lafleur et al. 2009). It activates ADAM10-dependent cleavage activity of amyloid precursor protein (APP) (Xu et al. 2009). The biology of tetraspanins and how they interact with APP processing pathways have been reviewed (Seipold and Saftig 2016).		Tspan12 of Homo sapiens

8.A.40.1.21	Tetraspanin14 (Tspan14) of 270 aas and 4 TMSs. Interacts with disintegrin and metalloprotease 10 (ADAM10), a ubiquitously expressed transmembranemetalloprotease that cleaves the extracellular regions from its transmembrane substrates (Noy et al. 2016). ADAM10 is essential for embryonic development and is implicated in cancer, Alzheimer's disease, and inflammatory diseases. The tetraspanins are a superfamily of 33 four-transmembrane proteins in mammals, of which the TspanC8 subgroup (Tspan5, 10, 14, 15, 17, and 33) promote ADAM10 intracellular trafficking and enzymatic maturation (Jouannet et al. 2016).		TspanC8 of Homo sapiens

8.A.40.1.22	Tetraspan-9, Tspan9, of 239 aas and 4 TMSs. Plays a role in aggregation and secretion induced by the platelet collagen receptor, GPVI, despite normal surface GPVI expression levels. This is because Tspan9 plays a role in platelet activation by regulating GPVI membrane dynamics (Haining et al. 2017).		Tspan9 of Homo sapiens

8.A.40.1.23	Tetraspannin, Tspan18 of 248 aas and 4 TMSs in a 3 + 1 arrangement. It is a regulator of Orai1, a store-operated Ca²⁺ channels in the plasma membrane which is critical to cell function. Orai1 loss causes severe immunodeficiency and developmental defects (Noy et al. 2018).		Tspan18 of Homo sapiens

8.A.40.1.24	Uncharacterized protein of 258 aas and 4 TMSs		UP of Stentor coeruleus

8.A.40.1.3	Peripherin-2 of 346 aas and 4 TMSs; Rod outer segment membrane protein; RDS; PRDH2. Causes retenal degeneration. Links rhodopsin (TC# 9.A.14.1.2) to a cyclic nucleotide-dependent channel (TC# 1.A.1.5.3) in the outer segments of rod photoreceptors. The G266D retinitis pigmentosa mutation in TMS4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014).	Animals	*Peripherin-2 of Homo sapiens* (P23942)**

8.A.40.1.4	Late bloomer; facilitates synapse and cell junction formation	Animals	*Late bloomer of Drosophila melanogaster* (Q24188)**

8.A.40.1.5	CD63 antigen-like tetraspanin. Involved in trafficking and transport regulation (Pols and Klumperman 2009).	Animals	*CD63-like protein of Schistosoma mansoni* (G4VD44)**

8.A.40.1.6	Tetraspannin, Tsp3A; involved in phagocytosis; engulfment.	Animals	Tsp3A of Drosophila melanogaster

8.A.40.1.7	Tetraspannin, Tsp42Fi	Animals	Tsp42Fi of Drosophila melanogaster

8.A.40.1.8	Tretraspanin-13. TSPAN-13 (NET6, TM4F13, UNC260,PRO296) specifically modulates the efficiency of coupling between voltage sensor activation and pore opening of the CaV2.2 α-subunit channel and accelerates the voltage-dependent activation and inactivation of the Ba²⁺current through CaV2.2. TSPAN-13 may regulate CaV2.2 Ca²⁺ channel activity in defined synaptic membrane compartments and thereby influences transmitter release (Mallmann et al. 2013; Lacinova et al. 2020). The human ortholog is 96% identical to the mouse protein.	Animals	Tetraspanin-13 of Mus musculus

8.A.40.1.9	Tetraspanin 29 (TSPAN29; CD9 antigen; GIG2; leucocyte antigen MIC3) of 228 aas and 4 TMSs. Plays a role in mast cell chemotaxis (Hálová et al. 2013). Also required for egg-sperm interactions during cell-cell fusion (Sabetian et al. 2014). It is associated with integrins, which regulates different processes, such as sperm-egg fusion, platelet activation and aggregation, and cell adhesion (Ikeyama et al. 1993, Higginbottom et al. 2003, Nakazawa et al. 2008). In myoblasts, it associates with CD81 and PTGFRN and inhibits myotube fusion during muscle regeneration. In macrophages, it associates with CD81 and beta-1 and beta-2 integrins, to prevent macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles (Takeda et al. 2003).	Animals	Tetraspanin 29 of Homo sapiens

Examples:
TC#	Name	Organismal Type	Example
8.A.40.2.1	Tetraspanin	Fungi	*Tetraspanin of Neurospora crassa* (Q8J0D3)**

8.A.40.2.2	Tetraspanin	Fungi	*Tetraspanin of Melampsora laricipopulina* (F4S576)**

8.A.40.2.3	Similar to tetraspanin	Fungi	Tetraspanin homologue of Leptosphaeria maculans

Examples:
TC#	Name	Organismal Type	Example
8.A.40.3.1	Tetraspanin family protein of 390 aas and 4 TMSs in a 3 + 1 TMS arrangemet.	Ciliates	Tetraspanin of Tetrahymena thermophila

8.A.40.3.2	Uncharacterized protein of 318 aas and 4 TMSs in a 3 + 1 TMS arrangement.		UP of Pseudocohnilembus persalinus

8.A.40.3.3	Uncharacterized protein of 316 aas and 4 TMSs in a 3 + 1 TMS arrangement.		UP of Stentor coeruleus

8.A.40.3.4	Uncharacterized protein showing sequence similarity with CD9, CD81, CD82 and CD151 of 332 aas and 4 TMSs in a 3 + 1 TMS arrangement.		UP of Stylonychia lemnae

8.A.40.3.5	Uncharacterized protein of 396 aas and 4 TMSs in a 3 + 1 TMS arrangement.		UP of Halteria grandinella

Examples:
TC#	Name	Organismal Type	Example
8.A.40.4.1	Putative senescence-associated protein of 285 aas and 4 TMSs in a 3 + 1 TMS arrangement.	Plants	Putative senescence-associated protein of Oryza sativa

8.A.40.4.2	*Tetraspanin-10 of 284 aas and 4 TMSs (Boavida et al.* 2013).**	Plants	Tetraspanin-18 of Arabidopsis thaliana

8.A.40.4.3	*Tetraspanin-16 of 248 aas and 4 TMSs (Boavida et al.* 2013).**	Plants	Tetraspanin-16 of Arabidopsis thaliana

8.A.40.4.4	*Tetraspanin-8-like protein of 270 aas and 4 putative TMSs. TETRASPANIN 8-1 from Phaseolus vulgaris* plays a key role during mutualistic interactions (Parra-Aguilar et al. 2023).**		4 TMS protein of Camellia sinensis

Examples:
TC#	Name	Organismal Type	Example
8.A.40.5.1	*Tetraspanin-20 of 281 aas and 4 TMSs (Boavida et al.* 2013).**	Plants	Tetraspanin-20 of Arabidopsis thaliana

8.A.40.5.2	*Tetraspanin 18 of 270 aas and 4 TMSs (Boavida et al.* 2013).**	Plants	Tetraspanin-18 of Arabidopsis thaliana

Examples:
TC#	Name	Organismal Type	Example
8.A.40.6.1	*Tetraspanin-14 of 260 aas and 4 TMSs (Boavida et al.* 2013).**	Plants	Tetraspanin-14 of Arabidopsis thaliana

8.A.40.6.2	*Tetraspanin-15 of 317 aas and 4 TMSs (Boavida et al.* 2013).**	Plants	Tetraspanin-15 of Arabidopsis thaliana

Examples:
TC#	Name	Organismal Type	Example
8.A.40.7.1	Uroplakin 1a (UPK1A or TSPAN21) of 258 aas and 4 TMSs in a 3 + 1 arrangement. Component of the asymmetric unit membrane (AUM), a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play a role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells (Chicote et al. 2017).		UPK1A of Homo sapiens

8.A.40.7.2	Uroplakin 1b, UPK1B of 260 aas and 4 TMSs in a 3 + 1 arrangement. Like UPK1A, it may be a component of the asymmetric unit membrane (AUM), a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells (Chicote et al. 2017). Proper formation of helical bundles consisting of the 4 tetraspanin TMSs seems to be a prerequisite for UPIb to exit from the ER into the plasma membrane (Tu et al. 2006).		UKB1B of Homo sapiens