Abstract:Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetylglucosaminyltransferase-1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNac-… Show more
“…Such competing action of the two enzymes eventually influences the resulting affinity towards laminin and other α-DG binding partners in different tissues [ 21 ]. A further complexity in the control of matriglycan synthesis emerged with the recent finding that also the kinase POMK is needed to regulate the LARGE1-mediated elongation of matriglycan [ 22 ]. Figure 1 A scheme of the M3 core carbohydrate chain and its specific carbohydrate blocks ( a ) and of the progressive enzymatic cascades present in the ER and Golgi apparatus ( b ).…”
Section: Introductionmentioning
confidence: 99%
“…The last step of this ER enzymatic phase is carried out by POMK (SGK196), a kinase that works with ATP as a donor substrate and is involved in the phosphorylation of the M3 glycan mannose on its C-6 position [ 44 ]. Three-dimensional structures of POMK have been solved [ 45 , 46 ], and it was recently shown that LARGE1 (see paragraph 1.3) can work efficiently only when POMK is active [ 22 ].…”
The dystroglycan (DG) complex plays a pivotal role for the stabilization of muscles in Metazoa. It is formed by two subunits, extracellular α-DG and transmembrane β-DG, originating from a unique precursor via a complex post-translational maturation process. The α-DG subunit is extensively glycosylated in sequential steps by several specific enzymes and employs such glycan scaffold to tightly bind basement membrane molecules. Mutations of several of these enzymes cause an alteration of the carbohydrate structure of α-DG, resulting in severe neuromuscular disorders collectively named dystroglycanopathies. Given the fundamental role played by DG in muscle stability, it is biochemically and clinically relevant to investigate these post-translational modifying enzymes from an evolutionary perspective. A first phylogenetic history of the thirteen enzymes involved in the fabrication of the so-called ‘M3 core’ laminin-binding epitope has been traced by an overall sequence comparison approach, and interesting details on the primordial enzyme set have emerged, as well as substantial conservation in Metazoa. The optimization along with the evolution of a well-conserved enzymatic set responsible for the glycosylation of α-DG indicate the importance of the glycosylation shell in modulating the connection between sarcolemma and surrounding basement membranes to increase skeletal muscle stability, and eventually support movement and locomotion.
“…Such competing action of the two enzymes eventually influences the resulting affinity towards laminin and other α-DG binding partners in different tissues [ 21 ]. A further complexity in the control of matriglycan synthesis emerged with the recent finding that also the kinase POMK is needed to regulate the LARGE1-mediated elongation of matriglycan [ 22 ]. Figure 1 A scheme of the M3 core carbohydrate chain and its specific carbohydrate blocks ( a ) and of the progressive enzymatic cascades present in the ER and Golgi apparatus ( b ).…”
Section: Introductionmentioning
confidence: 99%
“…The last step of this ER enzymatic phase is carried out by POMK (SGK196), a kinase that works with ATP as a donor substrate and is involved in the phosphorylation of the M3 glycan mannose on its C-6 position [ 44 ]. Three-dimensional structures of POMK have been solved [ 45 , 46 ], and it was recently shown that LARGE1 (see paragraph 1.3) can work efficiently only when POMK is active [ 22 ].…”
The dystroglycan (DG) complex plays a pivotal role for the stabilization of muscles in Metazoa. It is formed by two subunits, extracellular α-DG and transmembrane β-DG, originating from a unique precursor via a complex post-translational maturation process. The α-DG subunit is extensively glycosylated in sequential steps by several specific enzymes and employs such glycan scaffold to tightly bind basement membrane molecules. Mutations of several of these enzymes cause an alteration of the carbohydrate structure of α-DG, resulting in severe neuromuscular disorders collectively named dystroglycanopathies. Given the fundamental role played by DG in muscle stability, it is biochemically and clinically relevant to investigate these post-translational modifying enzymes from an evolutionary perspective. A first phylogenetic history of the thirteen enzymes involved in the fabrication of the so-called ‘M3 core’ laminin-binding epitope has been traced by an overall sequence comparison approach, and interesting details on the primordial enzyme set have emerged, as well as substantial conservation in Metazoa. The optimization along with the evolution of a well-conserved enzymatic set responsible for the glycosylation of α-DG indicate the importance of the glycosylation shell in modulating the connection between sarcolemma and surrounding basement membranes to increase skeletal muscle stability, and eventually support movement and locomotion.
“…Therefore, their amino acid sequences were well enough conserved with the canonical kinases for them to be classified as kinases. POMK is an O-mannose kinase important for dystroglycan receptor function and matriglycan elongation ( 18 , 20 ). VLK is the first secreted tyrosine kinase identified, and it phosphorylates a broad range of secreted and ER-resident substrates ( 19 ).…”
The study of extracellular phosphorylation was initiated in late 19th century when the secreted milk protein, casein, and egg-yolk protein, phosvitin, were shown to be phosphorylated. However, it took more than a century to identify Fam20C, which phosphorylates both casein and phosvitin under physiological conditions. This kinase, along with its family members Fam20A and Fam20B, defined a new family with altered amino acid sequences highly atypical from the canonical 540 kinases comprising the kinome. Fam20B is a glycan kinase that phosphorylates xylose residues and triggers peptidoglycan biosynthesis, a role conserved from sponges to human. The protein kinase, Fam20C, conserved from nematodes to humans, phosphorylates well over 100 substrates in the secretory pathway with overall functions postulated to encompass endoplasmic reticulum homeostasis, nutrition, cardiac function, coagulation, and biomineralization. The preferred phosphorylation motif of Fam20C is SxE/pS, and structural studies revealed that related member Fam20A allosterically activates Fam20C by forming a heterodimeric/tetrameric complex. Fam20A, a pseudokinase, is observed only in vertebrates. Loss-of-function genetic alterations in the Fam20 family lead to human diseases such as amelogenesis imperfecta, nephrocalcinosis, lethal and nonlethal forms of Raine syndrome with major skeletal defects, and altered phosphate homeostasis. Together, these three members of the Fam20 family modulate a diverse network of secretory pathway components playing crucial roles in health and disease. The overarching theme of this review is to highlight the progress that has been made in the emerging field of extracellular phosphorylation and the key roles secretory pathway kinases play in an ever-expanding number of cellular processes.
“…NG2 PG binds type V and VI collagen through its central non-globular domain ( Clarke et al, 2012 ; Huang et al, 2014 ) and with integrins ( Sakry and Trotter, 2016 ). C-terminal LamG domains of NG2 interact with BM components and are crucial for formation of synaptic neuroligin-neurexin complexes and glial cell signaling ( Jeong et al, 2017 ) and also interact with matriglycan-dystroglycan, perlecan, agrin and type XVIII collagen to localize NG2PG in motor neuron endplates in the neuromuscular junction (NMJ) ( Walimbe et al, 2020 ).…”
Section: Other Non-lectican Large Neural Proteoglycansmentioning
Chondroitin sulfate (CS) is the most abundant and widely distributed glycosaminoglycan (GAG) in the human body. As a component of proteoglycans (PGs) it has numerous roles in matrix stabilization and cellular regulation. This chapter highlights the roles of CS and CS-PGs in the central and peripheral nervous systems (CNS/PNS). CS has specific cell regulatory roles that control tissue function and homeostasis. The CNS/PNS contains a diverse range of CS-PGs which direct the development of embryonic neural axonal networks, and the responses of neural cell populations in mature tissues to traumatic injury. Following brain trauma and spinal cord injury, a stabilizing CS-PG-rich scar tissue is laid down at the defect site to protect neural tissues, which are amongst the softest tissues of the human body. Unfortunately, the CS concentrated in gliotic scars also inhibits neural outgrowth and functional recovery. CS has well known inhibitory properties over neural behavior, and animal models of CNS/PNS injury have demonstrated that selective degradation of CS using chondroitinase improves neuronal functional recovery. CS-PGs are present diffusely in the CNS but also form denser regions of extracellular matrix termed perineuronal nets which surround neurons. Hyaluronan is immobilized in hyalectan CS-PG aggregates in these perineural structures, which provide neural protection, synapse, and neural plasticity, and have roles in memory and cognitive learning. Despite the generally inhibitory cues delivered by CS-A and CS-C, some CS-PGs containing highly charged CS disaccharides (CS-D, CS-E) or dermatan sulfate (DS) disaccharides that promote neural outgrowth and functional recovery. CS/DS thus has varied cell regulatory properties and structural ECM supportive roles in the CNS/PNS depending on the glycoform present and its location in tissue niches and specific cellular contexts. Studies on the fruit fly, Drosophila melanogaster and the nematode Caenorhabditis elegans have provided insightful information on neural interconnectivity and the role of the ECM and its PGs in neural development and in tissue morphogenesis in a whole organism environment.
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