肌营养不良蛋白 - 糖蛋白复合物的形成
中文名称
通路描述
肌营养不良蛋白 - 糖蛋白复合物（DGC，也称为 DAPC，肌营养不良相关蛋白复合物）是一种位于细胞膜附近的由蛋白质和糖蛋白组成的大型多聚体复合物，连接细胞内细胞骨架与细胞外基质和层粘连蛋白（综述：Bhat 等，2018）。在肌肉细胞中，DGC 在稳定肌膜和传递机械刺激方面发挥作用（综述：Wilson 等，2022），但 DGC 复合物存在于多种细胞类型和组织中，在膜稳定性、信号转导和组织离子通道和 GABA 通道的组织方面发挥更广泛的作用（综述：Waite 等，2012；Gawor 和 PrózyÅski，2018；Bhat 等，2018）。虽然 DGC 某些成分的突变会导致肌肉纤维更易受损，引发如杜氏肌营养不良、贝克尔肌营养不良、肢体带肌营养不良和心肌病等不同类型的肌肉疾病（Straub 和 Campbell，1997；Cohn 和 Campbell，2000），但 DGC 成分也与非肌肉组织的疾病有关（Gumerson 和 Michele，2011）。DGC 的核心由 DAG1（糖蛋白）、DMD（肌营养不良蛋白）和 Utrophin 组成。DAG1 以非共价形式存在，由在丝氨酸 654 处切割后的 alpha 和 beta 链组成。外周 alpha-DAG1（30-653）通过与层粘连蛋白之间的 O-连接糖基化相互作用接触细胞外基质，而跨膜 beta-DAG1（684-895）与细胞质肌营养不良蛋白 DMD 相互作用。DGC 还包括一个跨膜肌球蛋白复合物，由四种肌球蛋白蛋白和 SSPN（肌球蛋白丝蛋白）组成。在细胞内侧，DMD 和 beta-DAG1 招募膜附着的细胞质蛋白，包括肌球蛋白（DTN）和肌球蛋白（SNT）家族成员（综述：Bhat 等，2018）。
英文描述
Elastic fibre formation Elastic fibres (EF) are a major structural constituent of dynamic connective tissues such as large arteries and lung parenchyma, where they provide essential properties of elastic recoil and resilience. EF are composed of a central cross-linked core of elastin, surrounded by a mesh of microfibrils, which are composed largely of fibrillin. In addition to elastin and fibrillin-1, over 30 ancillary proteins are involved in mediating important roles in elastic fibre assembly as well as interactions with the surrounding environment. These include fibulins, elastin microfibril interface located proteins (EMILINs), microfibril-associated glycoproteins (MAGPs) and Latent TGF-beta binding proteins (LTBPs). Fibulin-5 for example, is expressed by vascular smooth muscle cells and plays an essential role in the formation of elastic fibres through mediating interactions between elastin and fibrillin (Yanigasawa et al. 2002, Freeman et al. 2005). In addition, it plays a role in cell adhesion through integrin receptors and has been shown to influence smooth muscle cell proliferation (Yanigasawa et al. 2002, Nakamura et al. 2002). EMILINs are a family of homologous glycoproteins originally identified in extracts of aortas. Found at the elastin-fibrillin interface, early studies showed that antibodies to EMILIN can affect the process of elastic fibre formation (Bressan et al. 1993). EMILIN1 has been shown to bind elastin and fibulin-5 and appears to coordinate their common interaction (Zanetti et al. 2004). MAGPs are found to co-localize with microfibrils. MAGP-1, for example, binds strongly to an N-terminal sequence of fibrillin-1. Other proteins found associated with microfibrils include vitronectin (Dahlback et al. 1990).
Fibrillin is most familiar as a component of elastic fibres but microfibrils with no elastin are found in the ciliary zonules of the eye and invertebrate circulatory systems. The addition of elastin to microfibrils is a vertebrate adaptation to high pulsatile pressures in their closed circulatory systems (Faury et al. 2003). Elastin appears to have emerged after the divergence of jawless vertebrates from other vertebrates (Sage 1982).
Fibrillin-1 is the major structural component of microfibrils. Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. It was first isolated from human brain (Corson et al. 2004).
Fibrillin assembly is not as well defined as elastin assembly. The primary structure of fibrillin is dominated by calcium binding epidermal growth factor like repeats (Kielty et al. 2002). Fibrillin may form dimers or trimers before secretion. However, multimerisation predominantly occurs outside the cell. Formation of fibrils appears to require cell surface structures suggesting an involvement of cell surface receptors. Fibrillin is assembled pericellularly (i.e. on or close to the cell surface) into microfibrillar arrays that undergo time dependent maturation into microfibrils with beaded-string appearance. Transglutaminase forms gamma glutamyl epsilon lysine isopeptide bonds within or between peptide chains. Additionally, intermolecular disulfide bond formation between fibrillins is an important contributor to fibril maturation (Reinhardt et al. 2000).
Models of fibrillin-1 microfibril structure suggest that the N-terminal half of fibrillin-1 is asymmetrically exposed in outer filaments, while the C-terminal half is buried in the interior (Kuo et al. 2007). Fibrillinopathies include Marfan syndrome, familial ectopia lentis, familial thoracic aneurysm, all due to mutations in the fibrillin-1 gene FBN1, and congenital contractural arachnodactyly which is caused by mutation of FBN2 (Maslen & Glanville 1993, Davis & Summers 2012).
In vivo assembly of fibrillin requires the presence of extracellular fibronectin fibres (Sabatier et al. 2009). Fibrillins have Arg-Gly-Asp (RGD) sequences that interact with integrins (Pfaff et al. 1996, Sakamoto et al. 1996, Bax et al., 2003, Jovanovic et al. 2008) and heparin-binding domains that interact with a cell-surface heparan sulfate proteoglycan (Tiedemann et al. 2001) possibly a syndecan (Ritty et al. 2003). Fibrillins also have a major role in binding and sequestering growth factors such as TGF beta into the ECM (Neptune et al. 2003). Proteoglycans such as versican (Isogai et al. 2002), biglycan, and decorin (Reinboth et al. 2002) can interact with the microfibrils. They confer specific properties including hydration, impact absorption, molecular sieving, regulation of cellular activities, mediation of growth factor association, and release and transport within the extracellular matrix (Buczek-Thomas et al. 2002). In addition, glycosaminoglycans have been shown to interact with tropoelastin through its lysine side chains (Wu et al. 1999), regulating tropoelastin assembly (Tu & Weiss 2008).
Elastin is synthesized as a 70kDa monomer called tropoelastin, a highly hydrophobic protein composed largely of two types of domains that alternate along the polypeptide chain. Hydrophobic domains are rich in glycine, proline, alanine, leucine and valine. These amino acids occur in characteristic short (3-9 amino acids) tandem repeats, with a flexible and highly dynamic structure (Floquet et al. 2004). Unlike collagen, glycine in elastin is not rigorously positioned every 3 residues. However, glycine is distributed frequently throughout all hydrophobic domains of elastin, and displays a strong preference for inter-glycine spacing of 0-3 residues (Rauscher et al. 2006).
Elastic fibre formation involves the deposition of tropoelastin onto a template of fibrillin rich microfibrils. Recent results suggest that the first step of elastic fiber formation is the organization of small globules of elastin on the cell surface followed by globule aggregation into microfibres (Kozel et al. 2006). An important contribution to the initial stages assembly is thought to be made by the intrinsic ability of the protein to direct its own polymeric organization in a process termed 'coacervation' (Bressan et al. 1986). This self-assembly process appears to be determined by interactions between hydrophobic domains (Bressan et al. 1986, Vrhovski et al. 1997, Bellingham et al. 2003, Cirulis & Keeley 2010) which result in alignment of the cross-linking domains, allowing the stabilization of elastin through the formation of cross-links generated through the oxidative deamination of lysine residues, catalyzed by members of the lysyl oxidase (LOX) family (Reiser et al. 1992, Mithieux & Weiss 2005). The first step in the cross-linking reaction is the oxidative formation of the delta aldehyde, known as alpha aminoadipic semialdehyde or allysine (Partridge 1963). Subsequent reactions that are probably spontaneous lead to the formation of cross-links through dehydrolysinonorleucine and allysine aldol, a trifunctional cross-link dehydromerodesmosine and two tetrafunctional cross-links desmosine and isodesmosine (Lucero & Kagan 2006), which are unique to elastin. These cross-links confer mechanical integrity and high durability. In addition to their role in self-assembly, hydrophobic domains provide elastin with its elastomeric properties, with initial studies suggesting that the elastomeric propereties of elastin are driven through changes in entropic interactions with surrounding water molecules (Hoeve & Flory 1974).
A very specific set of proteases, broadly grouped under the name elastases, is responsible for elastin remodelling (Antonicelli et al. 2007). The matrix metalloproteinases (MMPs) are particularly important in elastin breakdown, with MMP2, 3, 9 and 12 explicitly shown to degrade elastin (Ra & Parks 2007). Nonetheless, elastin typically displays a low turnover rate under normal conditions over a lifetime (Davis 1993).
Fibrillin is most familiar as a component of elastic fibres but microfibrils with no elastin are found in the ciliary zonules of the eye and invertebrate circulatory systems. The addition of elastin to microfibrils is a vertebrate adaptation to high pulsatile pressures in their closed circulatory systems (Faury et al. 2003). Elastin appears to have emerged after the divergence of jawless vertebrates from other vertebrates (Sage 1982).
Fibrillin-1 is the major structural component of microfibrils. Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. It was first isolated from human brain (Corson et al. 2004).
Fibrillin assembly is not as well defined as elastin assembly. The primary structure of fibrillin is dominated by calcium binding epidermal growth factor like repeats (Kielty et al. 2002). Fibrillin may form dimers or trimers before secretion. However, multimerisation predominantly occurs outside the cell. Formation of fibrils appears to require cell surface structures suggesting an involvement of cell surface receptors. Fibrillin is assembled pericellularly (i.e. on or close to the cell surface) into microfibrillar arrays that undergo time dependent maturation into microfibrils with beaded-string appearance. Transglutaminase forms gamma glutamyl epsilon lysine isopeptide bonds within or between peptide chains. Additionally, intermolecular disulfide bond formation between fibrillins is an important contributor to fibril maturation (Reinhardt et al. 2000).
Models of fibrillin-1 microfibril structure suggest that the N-terminal half of fibrillin-1 is asymmetrically exposed in outer filaments, while the C-terminal half is buried in the interior (Kuo et al. 2007). Fibrillinopathies include Marfan syndrome, familial ectopia lentis, familial thoracic aneurysm, all due to mutations in the fibrillin-1 gene FBN1, and congenital contractural arachnodactyly which is caused by mutation of FBN2 (Maslen & Glanville 1993, Davis & Summers 2012).
In vivo assembly of fibrillin requires the presence of extracellular fibronectin fibres (Sabatier et al. 2009). Fibrillins have Arg-Gly-Asp (RGD) sequences that interact with integrins (Pfaff et al. 1996, Sakamoto et al. 1996, Bax et al., 2003, Jovanovic et al. 2008) and heparin-binding domains that interact with a cell-surface heparan sulfate proteoglycan (Tiedemann et al. 2001) possibly a syndecan (Ritty et al. 2003). Fibrillins also have a major role in binding and sequestering growth factors such as TGF beta into the ECM (Neptune et al. 2003). Proteoglycans such as versican (Isogai et al. 2002), biglycan, and decorin (Reinboth et al. 2002) can interact with the microfibrils. They confer specific properties including hydration, impact absorption, molecular sieving, regulation of cellular activities, mediation of growth factor association, and release and transport within the extracellular matrix (Buczek-Thomas et al. 2002). In addition, glycosaminoglycans have been shown to interact with tropoelastin through its lysine side chains (Wu et al. 1999), regulating tropoelastin assembly (Tu & Weiss 2008).
Elastin is synthesized as a 70kDa monomer called tropoelastin, a highly hydrophobic protein composed largely of two types of domains that alternate along the polypeptide chain. Hydrophobic domains are rich in glycine, proline, alanine, leucine and valine. These amino acids occur in characteristic short (3-9 amino acids) tandem repeats, with a flexible and highly dynamic structure (Floquet et al. 2004). Unlike collagen, glycine in elastin is not rigorously positioned every 3 residues. However, glycine is distributed frequently throughout all hydrophobic domains of elastin, and displays a strong preference for inter-glycine spacing of 0-3 residues (Rauscher et al. 2006).
Elastic fibre formation involves the deposition of tropoelastin onto a template of fibrillin rich microfibrils. Recent results suggest that the first step of elastic fiber formation is the organization of small globules of elastin on the cell surface followed by globule aggregation into microfibres (Kozel et al. 2006). An important contribution to the initial stages assembly is thought to be made by the intrinsic ability of the protein to direct its own polymeric organization in a process termed 'coacervation' (Bressan et al. 1986). This self-assembly process appears to be determined by interactions between hydrophobic domains (Bressan et al. 1986, Vrhovski et al. 1997, Bellingham et al. 2003, Cirulis & Keeley 2010) which result in alignment of the cross-linking domains, allowing the stabilization of elastin through the formation of cross-links generated through the oxidative deamination of lysine residues, catalyzed by members of the lysyl oxidase (LOX) family (Reiser et al. 1992, Mithieux & Weiss 2005). The first step in the cross-linking reaction is the oxidative formation of the delta aldehyde, known as alpha aminoadipic semialdehyde or allysine (Partridge 1963). Subsequent reactions that are probably spontaneous lead to the formation of cross-links through dehydrolysinonorleucine and allysine aldol, a trifunctional cross-link dehydromerodesmosine and two tetrafunctional cross-links desmosine and isodesmosine (Lucero & Kagan 2006), which are unique to elastin. These cross-links confer mechanical integrity and high durability. In addition to their role in self-assembly, hydrophobic domains provide elastin with its elastomeric properties, with initial studies suggesting that the elastomeric propereties of elastin are driven through changes in entropic interactions with surrounding water molecules (Hoeve & Flory 1974).
A very specific set of proteases, broadly grouped under the name elastases, is responsible for elastin remodelling (Antonicelli et al. 2007). The matrix metalloproteinases (MMPs) are particularly important in elastin breakdown, with MMP2, 3, 9 and 12 explicitly shown to degrade elastin (Ra & Parks 2007). Nonetheless, elastin typically displays a low turnover rate under normal conditions over a lifetime (Davis 1993).
所含基因
18 个基因