A5081174902- Hereditary Neurological Disorders
- RNA Research and Splicing
- Mechanisms of cancer metastasis
- HER2/EGFR in Cancer Research
- RNA regulation and disease
- Endoplasmic Reticulum Stress and Disease
- Enzyme Structure and Function
- Cellular Mechanics and Interactions
- Cell Adhesion Molecules Research
- Toxin Mechanisms and Immunotoxins
- Digestive system and related health
- Skin and Cellular Biology Research
- Signaling Pathways in Disease
- Lipid Membrane Structure and Behavior
- Advanced NMR Techniques and Applications
- Fibroblast Growth Factor Research
- Magnesium in Health and Disease
- Monoclonal and Polyclonal Antibodies Research
- Nanoparticle-Based Drug Delivery
- Biochemical and Molecular Research
- Cellular transport and secretion
- Botulinum Toxin and Related Neurological Disorders
- Glycosylation and Glycoproteins Research
- Lipid metabolism and disorders
- Neurogenetic and Muscular Disorders Research
University of Oulu
2015-2025
University of Jyväskylä
2008-2012
A link between sites of cell adhesion and the cytoskeleton is essential for regulation shape, motility, signaling. Migfilin a recently identified adaptor protein that localizes at cell-cell cell-extracellular matrix sites, where it thought to provide by interacting with actin cross-linking filamin. Here we have used x-ray crystallography, NMR spectroscopy, protein-protein interaction studies investigate molecular basis migfilin binding We report N-terminal portion can bind all three human...
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...
Peripheral myelin protein 2 (Pmp2, P2 or Fabp8), a member of the fatty acid binding family, was originally described together with basic (Mbp P1) and zero (Mpz P0) as one most abundant proteins in peripheral nervous system (PNS). Although Pmp2 is predominantly expressed myelinated Schwann cells, its role glia currently unknown. To study function PNS biology, we have generated complete knockout mouse (Pmp2(-/-) ). Comprehensive characterization Pmp2(-/-) mice revealed temporary reduction...
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...
P2 is a fatty acid-binding protein expressed in vertebrate peripheral nerve myelin, where it may function bilayer stacking and lipid transport. binds to phospholipid membranes through its positively charged surface hydrophobic tip, accommodates acids inside barrel structure. The structure of human refined at the ultrahigh resolution 0.93 Å allows detailed structural analyses, including full organization an internal hydrogen-bonding network. orientation bound fatty-acid carboxyl group linked...
Filamins are actin filament cross-linking proteins composed of an N-terminal actin-binding domain and 24 immunoglobulin-like domains (IgFLNs). interact with numerous proteins, including the cytoplasmic plasma membrane signaling cell adhesion receptors. Thereby filamins mechanically functionally link to cytoskeleton. Most interactions have been mapped C-terminal IgFLNs 16-24. Similarly, as previously known compact pair IgFLNa20-21, two-domain fragments IgFLNa16-17 IgFLNa18-19 were more in...
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...
In pancreatic ductal adenocarcinoma cancer (PDAC) drug resistance is a severe clinical problem and patients relapse within few months after receiving the standard-of-care chemotherapy. One contributing factor to treatment desmoplastic nature of PDAC; tumours are surrounded by thick layers stroma composing up 90% tumour mass. This stroma, which mostly comprised extracellular matrix (ECM) proteins, secreted cancer-associated fibroblasts (CAFs) residing in microenvironment. However, mechanistic...
The proper formation and function of the myelin sheath, a proteolipid membrane multilayer, relies on coordinated action several key proteins. We studied how proteins from peripheral cytoplasmic apposition—myelin basic protein (MBP), tail zero (P0ct), 2 (P2)—interact with each other myelin‐like membranes using various techniques, such as small‐angle X‐ray diffraction, differential scanning calorimetry (DSC), surface plasmon resonance (SPR), electron live epifluorescence microscopy. DSC...
Filamins are large proteins that cross-link actin filaments and connect to other cellular components. The C-terminal rod 2 region of FLNa (filamin A) mediates dimerization interacts with several transmembrane receptors intracellular signalling adaptors. SAXS (small-angle X-ray scattering) experiments were used make a model six immunoglobulin-like domain fragment the (domains 16-21). This had surprising three-branched structural arrangement, where each branch was made tightly packed...
Juxtanodin, also called ermin, is an F-actin-binding protein expressed by oligodendrocytes, the myelin-forming cells of central nervous system. While juxtanodin carries a short conserved segment at its C terminus, it otherwise shares no similarity with known sequences. We carried out structural characterization recombinant in solution. Juxtanodin turned to be intrinsically disordered, as evidenced conventional and synchrotron radiation CD spectroscopy. Small-angle X-ray scattering indicated...
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...
Abstract The Shank proteins are crucial scaffolding elements of the post‐synaptic density ( PSD ). One best‐characterized domains in is PDZ domain, which binds to C‐terminal segments several other proteins. We carried out a detailed structural analysis Shank3 domain‐peptide complexes, understand determinants binding affinity towards different ligand Ligand peptides from four were cocrystallized with and affinities determined calorimetrically. In addition conserved class I interactions...
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...
Peripheral myelin protein 2 (P2) is a fatty acid‐binding expressed in vertebrate peripheral nervous system myelin, as well human astrocytes. Suggested functions of P2 include membrane stacking and lipid transport. Mutations the PMP2 gene, encoding P2, are associated with Charcot–Marie–Tooth disease (CMT). Recent studies have revealed three novel mutations CMT patients. To shed light on structure function these variants, we used X‐ray neutron crystallography, small‐angle scattering, circular...
Filamins are scaffold proteins that bind to various proteins, including the actin cytoskeleton, integrin adhesion receptors, and adaptor such as migfilin. Alternative splicing of filamin, largely constructed from 24 Ig-like domains, is thought have a role in regulating its interactions with other proteins. The filamin A splice variant-1 (FLNa var-1) lacks 41 amino acids, last β-strand domain 19, FLNa(19), first FLNa(20) was previously shown mask key binding site on FLNa(21). Here, we present...
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...
N‐myc downstream‐regulated gene 1 (NDRG1) is a tumour suppressor involved in vesicular trafficking and stress response. NDRG1 participates peripheral nerve myelination, mutations the lead to Charcot‐Marie‐Tooth neuropathy. The 43‐kDa considered as an inactive member of α/β hydrolase superfamily. In addition central fold domain, consists short N terminus C‐terminal region with three 10‐residue repeats. We determined crystal structure domain human characterised dynamics full‐length NDRG1....
Filamin A (FLNa) is a large dimeric protein that binds to actin filaments via its actin-binding domain (ABD). The crystal structure of this was solved at 3.2 Å resolution. adopts closed conformation typical other ABDs, but also forms dimer both in crystallization conditions and solution. shows the localization residues mutated patients with periventricular nodular heterotopia or otopalatodigital syndrome. Structural analysis predicts mutations types disorder may affect binding.
The myelin sheath is a multilayered membrane that surrounds and insulates axons in the nervous system. One of proteins specific to peripheral nerve P2, protein able stack lipid bilayers. With goal obtaining detailed information on structure–function relationship 14 structure-based mutated variants human P2 were generated produced. mutants designed potentially affect binding bilayers by P2. All also crystallized preliminary crystallographic data are presented. structural from will be combined...
Despite intense research, the causes of various neurological diseases remain enigmatic to date. A role for viral or bacterial infection and associated molecular mimicry has frequently been suggested in etiology diseases, including demyelinating autoimmune disorders, such as multiple sclerosis. Pathogen mimics myelin-derived peptides have described literature shown induce myelin responses animal models. We carried out a structural study on peptides, thereof from pathogens, aqueous...
Collagen XVIII (ColXVIII) is a non-fibrillar collagen and proteoglycan that exists in three isoforms: short, medium long. The long isoforms contain unique N-terminal domain of unknown function, DUF959, our sequence-based secondary structure predictions indicated DUF959 could be an intrinsically disordered domain. Recombinant produced mammalian cells consisted ∼50% glycans had molecular mass 63 kDa. Circular dichroism spectroscopy confirmed the character static light scattering monomeric...