The myelin sheath is a multilamellar plasma membrane extension of highly specialized glial cells laid down in regularly spaced segments along axons. Recent studies indicate that metabolically active and capable communicating with the underlying axon. To be functionally connected to neuron, oligodendrocytes maintain non-compacted as cytoplasmic nanochannels. Here, we used high-pressure freezing for electron microscopy study these regions within close their native state. We identified...

Abstract Compact myelin comprises most of the dry weight myelin, and its insulative nature is basis for saltatory conduction nerve impulses. The major dense line (MDL) a 3-nm compartment between two cytoplasmic leaflets stacked membranes, mostly occupied by basic protein (MBP) phase. MBP an abundant involved in demyelinating diseases, such as multiple sclerosis. association with lipid membranes has been studied decades, but MBP-driven formation MDL remains elusive at biomolecular level. We...

Abstract Compact myelin forms the basis of nerve insulation essential for higher vertebrates. Dozens membrane bilayers undergo tight stacking, and in peripheral nervous system, this is partially enabled by protein zero (P0). Consisting an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, cytoplasmic extension (P0ct), P0 harbours important task ensuring integrity compact compartment, referred to as intraperiod line. Several disease mutations resulting neuropathies...

Abstract The myelin sheath is an essential, multilayered membrane structure that insulates axons, enabling the rapid transmission of nerve impulses. tetraspan proteolipid protein (PLP) most abundant compact in central nervous system (CNS). integral PLP adheres membranes together and enhances compaction myelin, having a fundamental role stability axonal support. linked to severe CNS neuropathies, including inherited Pelizaeus-Merzbacher disease spastic paraplegia type 2, as well multiple...

The 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) is a highly abundant membrane-associated enzyme in the myelin sheath of vertebrate nervous system. CNPase member 2H phosphoesterase family and catalyzes formation 2'-nucleotide products from substrates; however, its physiological substrate function remain unknown. It likely that participates RNA metabolism myelinating cell. We solved crystal structures phosphodiesterase domain mouse CNPase, showing binding mode ligands active site....

Abstract Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in abundant peripheral myelin protein P2. These trigger abnormal structure, leading to reduced nerve conduction velocity, muscle weakness, distal limb atrophy. P2 a myelin-specific expressed by Schwann cells that binds fatty acids membranes, contributing lipid homeostasis. We studied molecular basis patient...

Myelin protein zero (P0), a type I transmembrane protein, is the most abundant in peripheral nervous system (PNS) myelin—the lipid-rich, periodic structure of membrane pairs that concentrically encloses long axonal segments. Schwann cells, myelinating glia PNS, express P0 throughout their development until formation mature myelin. In intramyelinic compartment, immunoglobulin-like domain bridges apposing membranes via homophilic adhesion, forming, as revealed by electron microscopy,...

Abstract 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) is an enzyme highly abundant in the central nervous system myelin of terrestrial vertebrates. The catalytic domain CNPase belongs to 2H phosphoesterase superfamily and catalyzes hydrolysis nucleoside monophosphates 2′-monophosphates. detailed reaction mechanism essential amino acids involved have been described earlier, but roles many vicinity active site remained unknown. Here, several mutants were studied using kinetics assays,...

Myelin is a multilayered proteolipid sheath wrapped around selected axons in the nervous system. Its constituent proteins play major roles forming of highly regular membrane structure. P2 myelin-specific protein fatty acid binding (FABP) superfamily, which able to stack lipid bilayers together, and it target for mutations human inherited neuropathy Charcot-Marie-Tooth disease. A conserved residue that has been proposed participate conformational changes FABPs Phe57. This thought be...

Activity-regulated cytoskeleton-associated protein (Arc) is a multidomain of retroviral origin with vital role in the regulation synaptic plasticity and memory formation mammals. However, mechanistic structural basis Arc function poorly understood. has an N-terminal domain (NTD) involved membrane binding C-terminal (CTD) that binds postsynaptic ligands. In addition, NTD CTD both oligomerisation, including assembly retrovirus-like capsids intercellular signalling. To obtain new tools for...

The major myelin protein expressed by the peripheral nervous system Schwann cells is zero (P0), which represents 50% of total content in myelin. This 30-kDa integral membrane consists an immunoglobulin (Ig)-like domain, a transmembrane helix, and 69-residue C-terminal cytoplasmic tail (P0ct). basic residues P0ct contribute to tight packing lipid bilayers, alterations affect how P0 functions as adhesion molecule necessary for stability compact Several neurodegenerative neuropathies are...

Schwann cells myelinate selected axons in the peripheral nervous system (PNS) and contribute to fast saltatory conduction via formation of compact myelin, which water is excluded from between tightly adhered lipid bilayers. Peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) Dejerine-Sottas syndrome (DSS), are incurable demyelinating conditions that result pain, decrease muscle mass, functional impairment. Many cell proteins, directly involved stability myelin or its...

Myelin protein P2 is a peripheral membrane of the fatty acid-binding family that functions in formation and maintenance nerve myelin sheath. Several gene mutations cause human Charcot-Marie-Tooth neuropathy, but mature sheath assembly mechanism unclear. Here, cryo-EM myelin-like proteolipid multilayers revealed an ordered three-dimensional (3D) lattice molecules between stacked lipid bilayers, visualizing supramolecular at major dense line. The data disclosed single layer inserted two...

The formation of a mature myelin sheath in the vertebrate nervous system requires specific protein-membrane interactions. Several myelin-specific proteins are involved stacking lipid membranes into multilayered structures around axons, and misregulation these processes may contribute to chronic demyelinating diseases. Two key membrane binding basic protein (MBP) zero (P0). Other factors, including Ca2+, important for regulation myelination. We studied effects ionic strength Ca2+ on...

The process of myelination in the nervous system requires coordinated formation both transient and stable supramolecular complexes. Myelin-specific proteins play key roles these assemblies, which may link membranes to each other or connect myelinating cell cytoskeleton extracellular matrix. myelin protein periaxin is known an important role linking Schwann basal lamina through membrane receptors, such as dystroglycan complex. Mutations that truncate from C terminus cause demyelinating...

The functions of the annexin family proteins involve binding to Ca2+, lipid membranes, other proteins, and RNA, annexins share a common folded core structure at C terminus. Annexin A11 (AnxA11) has long N-terminal region, which is predicted be disordered, binds forms membraneless organelles involved in neuronal transport. Mutations AnxA11 have been linked amyotrophic lateral sclerosis (ALS). We studied stability identified short stabilising segment end core, links domains I IV. crystal...

Hepatocyte nuclear factor 1A (HNF-1A) is a transcription expressed in several embryonic and adult tissues, modulating the expression of numerous target genes. Pathogenic variants HNF1A gene are known to cause maturity-onset diabetes young 3 (MODY3 or MODY), disease characterized by dominant inheritance, age onset before 25 35 years age, pancreatic β-cell dysfunction. A precise diagnosis can alter management this disease, as insulin be exchanged with sulfonylurea tablets genetic counseling...

Prolyl 4-hydroxylases (P4Hs) catalyze post-translational hydroxylation of peptidyl proline residues. In addition to collagen P4Hs and hypoxia-inducible factor P4Hs, a third P4H—the poorly characterized endoplasmic reticulum–localized transmembrane prolyl 4-hydroxylase (P4H-TM)—is found in animals. P4H-TM variants are associated with the familiar neurological HIDEA syndrome, but how these might contribute disease is unknown. Here, we explored this question structural functional analysis...

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. Despite involvement ganglioside-induced differentiation-associated protein 1 (GDAP1) in CMT, structure and function, as well pathogenic mechanisms, remain unclear. We determined crystal complete human GDAP1 core domain, which shows a novel mode dimerization within glutathione S-transferase (GST) family. The long GDAP1-specific insertion forms an extended helix flexible loop. catalytically inactive...

Numerous human proteins are classified as intrinsically disordered (IDPs). Due to their physicochemical properties, high-resolution structural information about IDPs is generally lacking. On the other hand, known adopt local ordered structures upon interactions with e.g. or lipid membrane surfaces. While recent developments in protein structure prediction have been revolutionary, impact on IDP research at high resolution remains limited. We took a specific example of two myelin-specific...