DOCSLIB.ORG

Plectin-Mediated Intermediate Filament Functions: Why Isoforms Matter

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Plectin-Mediated Intermediate Filament Functions: Why Isoforms Matter cells Review Plectin-Mediated Intermediate Filament Functions: Why Isoforms Matter Gerhard Wiche Max Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria; [email protected] Abstract: This essay focuses on the role of plectin and its various isoforms in mediating intermedi- ate filament (IF) network functions. It is based on previous studies that provided comprehensive evidence for a concept where plectin acts as an IF recruiter, and plectin-mediated IF networking and anchoring are key elements in IF function execution. Here, plectin’s global role as modulator of IF functionality is viewed from different perspectives, including the mechanical stabilization of IF networks and their docking platforms, contribution to cellular viscoelasticity and mechan- otransduction, compartmentalization and control of the actomyosin machinery, connections to the microtubule system, and mechanisms and specificity of isoform targeting. Arguments for IF net- works and plectin acting as mutually dependent partners are also given. Lastly, a working model is presented that describes a unifying mechanism underlying how plectin–IF networks mechanically control and propagate actomyosin-generated forces, affect microtubule dynamics, and contribute to mechanotransduction. Keywords: plectin; isoforms; intermediate filaments; mechanotransduction; actomyosin; microtubules Citation: Wiche, G. Plectin-Mediated 1. Introduction Intermediate Filament Functions: Why Isoforms Matter. Cells 2021, 10, Plectin, a cytolinker protein and member of the plakin protein family [1], was described 2154. https://doi.org/10.3390/ and first characterized some 40 years ago [2]. The protein was shown to play a central cells10082154 role in the organization and performance of the vertebrate cell cytoskeleton. Not only is it essential for the functionality of intermediate filament (IF) networks of different types, Academic Editor: Rudolf E. Leube but it also affects the dynamic behavior and site of action of the contractile and polarizing actomyosin and microtubule (MT) network systems [3–6]. With a polypeptide chain length Received: 3 August 2021 of ~4500 amino-acid residues, plectin is a huge multidomain protein, comprising a variable Accepted: 17 August 2021 N terminus, followed by a classical actin-binding domain (ABD) and a plakin domain, Published: 21 August 2021 a central helical rod domain, and a long C-terminal domain [5]. The ABD comprises a pair of calponin homology (CH) domains, and the plakin domain contains nine spectrin Publisher’s Note: MDPI stays neutral repeats with an SH3 domain embedded within the fifth repeat [7]. Via their central α-helical with regard to jurisdictional claims in domain, plectin molecules dimerize to form a ~200 nm long rod of a coiled-coil helical published maps and institutional affil- structure; the lateral association of rod domains leads to plectin oligomers. The C-terminal iations. domain is built up of six plectin repeat domains (PRDs) of roughly 300 residues each, separated by linker regions of variable sizes, and a short C-terminal tail. Within each PRD lies a highly conserved central core, and within the linker region between PRDs 5 and 6 resides plectin’s major IF-binding domain (IFBD) [8]. Copyright: © 2021 by the author. What makes plectin quite unique is its isoform diversity based on multiple variable Licensee MDPI, Basel, Switzerland. first exons alternatively splicing into a common exon 2, generating a hydra-like pattern This article is an open access article of alternative transcripts. There are about a dozen of such transcripts, sharing a common distributed under the terms and structure composed of over 30 exons, but differing from each other by their very N-terminal conditions of the Creative Commons head domains. Additional alternative splicing of small exons into plectin’s ABD and of Attribution (CC BY) license (https:// a single large exon (exon 31) encoding the entire α-helical coiled-coil rod domain of the creativecommons.org/licenses/by/ molecule gives rise to a multiplicity of plectin variants [9]. The isoforms encoded by 4.0/). Cells 2021, 10, 2154. https://doi.org/10.3390/cells10082154 https://www.mdpi.com/journal/cells Cells 2021, 10, 2154 2 of 21 of a single large exon (exon 31) encoding the entire α-helical coiled-coil rod domain of the Cells 2021, 10, 2154 molecule gives rise to a multiplicity of plectin variants [9]. The isoforms encoded2 ofby 21 these transcript variants were named according to their alternative first coding exons in chron- ological order of their identification. Accordingly, the first isoform identified was given thethese name transcript plectin isoform variants were1 (P1), named followed according by isoforms to their alternativeP1a, P1b, P1c, first codingetc., with exons P1k in being thechronological last isoform orderidentified of their (for identification. a more detailed Accordingly, description the of first isoforms isoform and identified corresponding was transcriptgiven the variants, name plectin see [5]). isoform 1 (P1), followed by isoforms P1a, P1b, P1c, etc., with P1kAs being shown the by last expression isoform identified profiling, (for different a more detailedtypes of description cells and tissues of isoforms express and these corresponding transcript variants, see [5]). isoforms in different combinations and proportions, often in dependence of their devel- As shown by expression profiling, different types of cells and tissues express these opmentalisoforms stage in different [10,11]. combinations The observation and proportions, of distinct oftenisoform in dependence expression ofpatterns their devel- has been theopmental basis for stagea working [10,11]. model The observation where the of expression distinct isoform of different expression sets patterns of plectin has isoforms been is tailoredthe basis for forparticular a working functional model where needs the of expression the cell, ofin differenta kind of sets “custom of plectin-made” isoforms fashion. Importantis tailored for for the particular understanding functional of needs plectin’s of the multiple cell, in a functions kind of “custom-made” was the observation fashion. that theImportant various isoform for the understanding-specific N-terminal of plectin’s head multiple domains functions dictate was the the cellular observation localization that of thethe isoform various [12], isoform-specific by dockingN to-terminal distinct head interaction domains partners. dictate the A cellular few isoform localization-specific of the inter- actionisoform partners [12], by have docking indeed to distinct been identified; interaction however, partners. A in few several isoform-specific other cases, interaction isoform-spe- partners have indeed been identified; however, in several other cases, isoform-specific cific interaction partners and targeting mechanisms are still unknown. As all the isoforms interaction partners and targeting mechanisms are still unknown. As all the isoforms are areendowed endowed with with a universala universal high high affinity affinity IF-binding IF-binding domain domain at their at theirC termini, C termini, they willthey will recruitrecruit and and anchor anchor IF IF networks networks ofof anyany type type to to the the various various sites sites and and structures structures with with which which theythey are are associated. associated. This This is anan important important concept, concept, as itas leads it leads to an to isoform-dependent an isoform-dependent inter- in- terlinkinglinking ofof different different cellular cellular structures structures and and organelles organelles via IFs, via with IFs, major with implications major implications for forcytoarchitecture, cytoarchitecture, shape, shape, polarization, polarization, and migrationand migration potential potential of cells [of4– 6cells,13]; [4 see–6,13]; Figure see1 Fig- urefor 1 for a schematic a schematic drawing drawing of the of plectin the plectin molecule molecule and its diverseand its head diverse domains). head domains). FigureFigure 1. Schematic 1. Schematic representation representation of ofa plectin a plectin dimer. dimer. The The NN--terminalterminal domain domain contains contains two two actin-binding actin-binding domains domains (ABDs) (ABDs) each consistingeach consisting of two of two calponin calponin homology homology domains domains (light (light and darkdark red),red), and and two two plakin plakin domains domains each each comprising comprising nine nine spectrinspectrin repeats repeats (green) (green) and and one one (noncanonical) (noncanonical) SH3 SH3 domain domain (yellow).(yellow). The The central central coiled-coil coiled-coil rod rod domain domain is ~200 is ~200 nm long. nm long. The CThe-terminalC-terminal domains domains each each contain contain six six plectin repeat repeat domains domains (PRDs), (PRDs), where where PRDs PRDs consist consist of a conserved of a conserved region, referred region, re- ferredto to as as module, module, and and a linker a linker region, region, one of one which of which harbors harbors the universal the universal IF-binding IF domain-binding (IFBD). domain The (IFBD). stars at theTheN starstermini at the N terminiof theof the polypeptide polypeptide chains chains stand forstand the differentfor the different isoform-specific isoform head-specific domains. head Nine domains. alternative Nine head alternative domains are head depicted domains are depicted(color-coded (color bars),-coded giving bars), the namegiving
Load more

Recommended publications
  • Desmin Interacts Directly with Mitochondria
    International Journal of Molecular Sciences Article Desmin Interacts Directly with Mitochondria Alexander A. Dayal 1, Natalia V. Medvedeva 1, Tatiana M. Nekrasova 1, Sergey D. Duhalin 1, Alexey K. Surin 1,2 and Alexander A. Minin 1,* 1 Institute of Protein Research of Russian Academy of Sciences, Vavilova st., 34, 119334 Moscow, Russia; [email protected] (A.A.D.); [email protected] (N.V.M.); [email protected] (T.M.N.); [email protected] (S.D.D.); [email protected] (A.K.S.) 2 Pushchino Branch, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki 6, Pushchino, 142290 Moscow Region, Russia * Correspondence: [email protected] Received: 14 October 2020; Accepted: 26 October 2020; Published: 30 October 2020 Abstract: Desmin intermediate filaments (IFs) play an important role in maintaining the structural and functional integrity of muscle cells. They connect contractile myofibrils to plasma membrane, nuclei, and mitochondria. Disturbance of their network due to desmin mutations or deficiency leads to an infringement of myofibril organization and to a deterioration of mitochondrial distribution, morphology, and functions. The nature of the interaction of desmin IFs with mitochondria is not clear. To elucidate the possibility that desmin can directly bind to mitochondria, we have undertaken the study of their interaction in vitro. Using desmin mutant Des(Y122L) that forms unit-length filaments (ULFs) but is incapable of forming long filaments and, therefore, could be effectively separated from mitochondria by centrifugation through sucrose gradient, we probed the interaction of recombinant human desmin with mitochondria isolated from rat liver. Our data show that desmin can directly bind to mitochondria, and this binding depends on its N-terminal domain.
    [Show full text]
  • PSPC1 Potentiates IGF1R Expression to Augment Cell Adhesion and Motility
    1 Supplementary information 2 PSPC1 potentiates IGF1R expression to augment cell 3 adhesion and motility 4 Hsin-Wei Jen1,2 , De-Leung Gu 2, Yaw-Dong Lang 2 and Yuh-Shan Jou 1,2,* 5 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 6 2 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 7 * Author to whom correspondence should be addressed 8 Cells 2020, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/cells Cells 2020, 9, x FOR PEER REVIEW 2 of 10 9 10 11 Supplementary Figure S1: Expression of IGF1R and integrin in PSPC1-expressing or PSPC1-depleted 12 HCC cells by Western blotting analysis 13 (A) Detection of IGF1R protein levels in three PSPC1-knockdown cells Huh7, HepG2 and Mahlavu. (B) 14 Detection of selected integrin expression in PSPC1-overexpressing or PSPC1-depleted HCC cells by using 15 their total cell lysates immunoblotted with specific integrin antibodies as shown. 16 17 18 Supplementary Figure S2: PSPC1-modulated IGF1R downstream signaling in HCC cells. Cells 2020, 9, x FOR PEER REVIEW 3 of 10 19 (A, B) Immunoblotting of IGF1R expression in PSPC1-overexpressing SK-Hep1 and PLC5 cells 20 treated with IGF1R shRNAs. (C, D) Cell migration and adhesion were measured in PSPC1- 21 knockdown Hep3B cells rescued with exogenous expression of IGF1R. Exogenous expression of 22 IGF1R in PSPC1-knockdown Hep3B cells were then applied for detection of altered AKT/ERK 23 signaling including (E) total PSPC1, IGF1R, AKT, ERK, p-IGF1R, p-AKT(S473), and 24 p-ERK(T202/Y204) as well as altered FAK/Src signaling including (F) total FAK, Src, p-FAK(Y397) 25 and p-Src(Y416) by immunoblotting assay.
    [Show full text]
  • The Desmoplakin Carboxyl Terminus Coaligns with and Specifically Disrupts Intermediate Filament Networks When Expressed in Cultured Cells Thaddeus S
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central The Desmoplakin Carboxyl Terminus Coaligns with and Specifically Disrupts Intermediate Filament Networks When Expressed in Cultured Cells Thaddeus S. Stappenbeck and Kathleen J. Green Department of Pathology and the Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 Abstract. Specific interactions between desmoplakins tides including the 90-kD carboxy-terminal globular I and 11 (DP I and II) and other desmosomal or cyto- domain of DP I specifically colocalized with and ulti- skeletal molecules have been difficult to determine in mately resulted in the complete disruption of IF in part because of the complexity and insolubility of the both cell lines. This effect was specific for IF as micro- desmosome and its constituents . We have used a mo- tubule and microfilament networks were unaltered . lecular genetic approach to investigate the role that This effect was also specific for the carboxyl terminus DP I and 11 may play in the association of the desmo- of DP, as the expression of the 95-kD rod domain of somal plaque with cytoplasmic intermediate filaments DP I did not visibly alter IF networks. Immunogold (IF) . A series of mammalian expression vectors en- localization of COS-7 cells transfected with constructs coding specific predicted domains of DP I were tran- including the carboxyl terminus of DP demonstrated siently expressed in cultured cells that form (COS-7) an accumulation of mutant protein in perinuclear aggre- and do not form (NIH-3T3) desmosomes. Sequence gates within which IF subunits were sequestered.
    [Show full text]
  • Human Plectin: Organization of the Gene, Sequence Analysis, and Chromosome Localization (8Q24) CHANG-GONG LIU*, CHRISTIAN MAERCKER*, MARIA J
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 4278-4283, April 1996 Biochemistry Human plectin: Organization of the gene, sequence analysis, and chromosome localization (8q24) CHANG-GONG LIU*, CHRISTIAN MAERCKER*, MARIA J. CASTANONt, RUDOLF HAUPTMANNt, AND GERHARD WICHE* *Institute of Biochemistry and Molecular Cell Biology, University of Vienna-Biocenter, 1030 Vienna, Austria; and tErnst Boehringer Institut, 1121 Vienna, Austria Communicated by Gottfried Schatz, Biozentrum der Universitat Basel, Basel, Switzerland, January 2, 1996 (received for review August 28, 1995) ABSTRACT Plectin, a 500-kDa intermediate filament C-terminal globular domain of the molecule (9). The overex- binding protein, has been proposed to provide mechanical pression of plectin mutant proteins containing this site(s) has strength to cells and tissues by acting as a cross-linking a dramatic dominant negative effect on cells, causing the total element of the cytoskeleton. To set the basis for future studies collapse of cytoplasmic IF networks. Based on the combined on gene regulation, tissue-specific expression, and patholog- information available to date, plectin has been proposed to ical conditions involving this protein, we have cloned the play a key role as a versatile cross-linking element of the human plectin gene, determined its coding sequence, and cytoskeleton. Particularly, because of its strategic localization established its genomic organization. The coding sequence at the cytoskeleton-plasma membrane interface, such as in all contains 32 exons that extend
    [Show full text]
  • Microtubule Plus-End Tracking Proteins in Neuronal Development
    Cell. Mol. Life Sci. (2016) 73:2053–2077 DOI 10.1007/s00018-016-2168-3 Cellular and Molecular Life Sciences REVIEW Microtubule plus-end tracking proteins in neuronal development 1 1 1 Dieudonne´e van de Willige • Casper C. Hoogenraad • Anna Akhmanova Received: 13 December 2015 / Revised: 4 February 2016 / Accepted: 22 February 2016 / Published online: 11 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Regulation of the microtubule cytoskeleton is AIS Axon initial segment of pivotal importance for neuronal development and BDNF Brain-derived neurotrophic factor function. One such regulatory mechanism centers on CAMSAP Calmodulin-regulated spectrin-associated microtubule plus-end tracking proteins (?TIPs): struc- protein turally and functionally diverse regulatory factors, which CAP-Gly Cytoskeletal-associated protein glycine-rich can form complex macromolecular assemblies at the CEP Centrosomal protein growing microtubule plus-ends. ?TIPs modulate important CFEOM1 Congenital fibrosis of the extraocular muscles properties of microtubules including their dynamics and type 1 their ability to control cell polarity, membrane transport CH Calponin homology and signaling. Several neurodevelopmental and neurode- CLASP Cytoplasmic linker protein-associated protein generative diseases are associated with mutations in ?TIPs CLIP Cytoplasmic linker protein or with misregulation of these proteins. In this review, we DRG Dorsal root ganglia focus on the role and regulation of ?TIPs in neuronal EB
    [Show full text]
  • Crosstalk Between Mitochondria and Cytoskeleton in Cardiac Cells
    cells Review Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells Andrey V. Kuznetsov 1,2,*, Sabzali Javadov 3 , Michael Grimm 1, Raimund Margreiter 4, Michael J. Ausserlechner 2 and Judith Hagenbuchner 5,* 1 Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria; [email protected] 2 Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 3 Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, USA; [email protected] 4 Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 5 Department of Paediatrics II, Medical University of Innsbruck, 6020 Innsbruck, Austria * Correspondence: [email protected] (A.V.K.); [email protected] (J.H.); Tel.: +43-512-504-27815 (A.V.K.); +43-512-504-81578 (J.H.) Received: 3 December 2019; Accepted: 13 January 2020; Published: 16 January 2020 Abstract: Elucidation of the mitochondrial regulatory mechanisms for the understanding of muscle bioenergetics and the role of mitochondria is a fundamental problem in cellular physiology and pathophysiology. The cytoskeleton (microtubules, intermediate filaments, microfilaments) plays a central role in the maintenance of mitochondrial shape, location, and motility. In addition, numerous interactions between cytoskeletal proteins and mitochondria can actively participate in the regulation of mitochondrial respiration and oxidative phosphorylation. In cardiac and skeletal muscles, mitochondrial positions are tightly fixed, providing their regular arrangement and numerous interactions with other cellular structures such as sarcoplasmic reticulum and cytoskeleton.
    [Show full text]
  • Keratins and Plakin Family Cytolinker Proteins Control the Length Of
    RESEARCH ARTICLE Keratins and plakin family cytolinker proteins control the length of epithelial microridge protrusions Yasuko Inaba*, Vasudha Chauhan, Aaron Paul van Loon, Lamia Saiyara Choudhury, Alvaro Sagasti* Molecular, Cell and Developmental Biology Department and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States Abstract Actin filaments and microtubules create diverse cellular protrusions, but intermediate filaments, the strongest and most stable cytoskeletal elements, are not known to directly participate in the formation of protrusions. Here we show that keratin intermediate filaments directly regulate the morphogenesis of microridges, elongated protrusions arranged in elaborate maze-like patterns on the surface of mucosal epithelial cells. We found that microridges on zebrafish skin cells contained both actin and keratin filaments. Keratin filaments stabilized microridges, and overexpressing keratins lengthened them. Envoplakin and periplakin, plakin family cytolinkers that bind F-actin and keratins, localized to microridges, and were required for their morphogenesis. Strikingly, plakin protein levels directly dictate microridge length. An actin-binding domain of periplakin was required to initiate microridge morphogenesis, whereas periplakin-keratin binding was required to elongate microridges. These findings separate microridge morphogenesis into distinct steps, expand our understanding of intermediate filament functions, and identify microridges as protrusions that integrate actin and intermediate filaments. *For correspondence: [email protected] (YI); Introduction [email protected] (AS) Cytoskeletal filaments are scaffolds for membrane protrusions that create a vast diversity of cell shapes. The three major classes of cytoskeletal elements—microtubules, actin filaments, and inter- Competing interests: The mediate filaments (IFs)—each have distinct mechanical and biochemical properties and associate authors declare that no with different regulatory proteins, suiting them to different functions.
    [Show full text]
  • Conserved Microtubule–Actin Interactions in Cell Movement and Morphogenesis
    REVIEW Conserved microtubule–actin interactions in cell movement and morphogenesis Olga C. Rodriguez, Andrew W. Schaefer, Craig A. Mandato, Paul Forscher, William M. Bement and Clare M. Waterman-Storer Interactions between microtubules and actin are a basic phenomenon that underlies many fundamental processes in which dynamic cellular asymmetries need to be established and maintained. These are processes as diverse as cell motility, neuronal pathfinding, cellular wound healing, cell division and cortical flow. Microtubules and actin exhibit two mechanistic classes of interactions — regulatory and structural. These interactions comprise at least three conserved ‘mechanochemical activity modules’ that perform similar roles in these diverse cell functions. Over the past 35 years, great progress has been made towards under- crosstalk occurs in processes that require dynamic cellular asymme- standing the roles of the microtubule and actin cytoskeletal filament tries to be established or maintained to allow rapid intracellular reor- systems in mechanical cellular processes such as dynamic shape ganization or changes in shape or direction in response to stimuli. change, shape maintenance and intracellular organelle movement. Furthermore, the widespread occurrence of these interactions under- These functions are attributed to the ability of polarized cytoskeletal scores their importance for life, as they occur in diverse cell types polymers to assemble and disassemble rapidly, and to interact with including epithelia, neurons, fibroblasts, oocytes and early embryos, binding proteins and molecular motors that mediate their regulated and across species from yeast to humans. Thus, defining the mecha- movement and/or assembly into higher order structures, such as radial nisms by which actin and microtubules interact is key to understand- arrays or bundles.
    [Show full text]
  • Plakoglobin Is Required for Effective Intermediate Filament Anchorage to Desmosomes Devrim Acehan1, Christopher Petzold1, Iwona Gumper2, David D
    ORIGINAL ARTICLE Plakoglobin Is Required for Effective Intermediate Filament Anchorage to Desmosomes Devrim Acehan1, Christopher Petzold1, Iwona Gumper2, David D. Sabatini2, Eliane J. Mu¨ller3, Pamela Cowin2,4 and David L. Stokes1,2,5 Desmosomes are adhesive junctions that provide mechanical coupling between cells. Plakoglobin (PG) is a major component of the intracellular plaque that serves to connect transmembrane elements to the cytoskeleton. We have used electron tomography and immunolabeling to investigate the consequences of PG knockout on the molecular architecture of the intracellular plaque in cultured keratinocytes. Although knockout keratinocytes form substantial numbers of desmosome-like junctions and have a relatively normal intercellular distribution of desmosomal cadherins, their cytoplasmic plaques are sparse and anchoring of intermediate filaments is defective. In the knockout, b-catenin appears to substitute for PG in the clustering of cadherins, but is unable to recruit normal levels of plakophilin-1 and desmoplakin to the plaque. By comparing tomograms of wild type and knockout desmosomes, we have assigned particular densities to desmoplakin and described their interaction with intermediate filaments. Desmoplakin molecules are more extended in wild type than knockout desmosomes, as if intermediate filament connections produced tension within the plaque. On the basis of our observations, we propose a particular assembly sequence, beginning with cadherin clustering within the plasma membrane, followed by recruitment of plakophilin and desmoplakin to the plaque, and ending with anchoring of intermediate filaments, which represents the key to adhesive strength. Journal of Investigative Dermatology (2008) 128, 2665–2675; doi:10.1038/jid.2008.141; published online 22 May 2008 INTRODUCTION dense plaque that is further from the membrane and that Desmosomes are large macromolecular complexes that mediates the binding of intermediate filaments.
    [Show full text]
  • Transiently Structured Head Domains Control Intermediate Filament Assembly
    Transiently structured head domains control intermediate filament assembly Xiaoming Zhoua, Yi Lina,1, Masato Katoa,b,c, Eiichiro Morid, Glen Liszczaka, Lillian Sutherlanda, Vasiliy O. Sysoeva, Dylan T. Murraye, Robert Tyckoc, and Steven L. McKnighta,2 aDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; bInstitute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology, 263-8555 Chiba, Japan; cLaboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520; dDepartment of Future Basic Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, Japan; and eDepartment of Chemistry, University of California, Davis, CA 95616 Contributed by Steven L. McKnight, January 2, 2021 (sent for review October 30, 2020; reviewed by Lynette Cegelski, Tatyana Polenova, and Natasha Snider) Low complexity (LC) head domains 92 and 108 residues in length are, IF head domains might facilitate filament assembly in a manner respectively, required for assembly of neurofilament light (NFL) and analogous to LC domain function by RNA-binding proteins in the desmin intermediate filaments (IFs). As studied in isolation, these IF assembly of RNA granules. head domains interconvert between states of conformational disor- IFs are defined by centrally located α-helical segments 300 to der and labile, β-strand–enriched polymers. Solid-state NMR (ss-NMR) 350 residues in length. These central, α-helical segments are spectroscopic studies of NFL and desmin head domain polymers re- flanked on either end by head and tail domains thought to be veal spectral patterns consistent with structural order.
    [Show full text]
  • Microtubule-Associated Protein Tau (Molecular Pathology/Neurodegenerative Disease/Neurofibriliary Tangles) M
    Proc. Nati. Acad. Sci. USA Vol. 85, pp. 4051-4055, June 1988 Medical Sciences Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau (molecular pathology/neurodegenerative disease/neurofibriliary tangles) M. GOEDERT*, C. M. WISCHIK*t, R. A. CROWTHER*, J. E. WALKER*, AND A. KLUG* *Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom; and tDepartment of Psychiatry, University of Cambridge Clinical School, Hills Road, Cambridge CB2 2QQ, United Kingdom Contributed by A. Klug, March 1, 1988 ABSTRACT Screening of cDNA libraries prepared from (21). This task is made all the more difficult because there is the frontal cortex ofan zheimer disease patient and from fetal no functional or physiological assay for the protein(s) of the human brain has led to isolation of the cDNA for a core protein PHF. The only identification so far possible is the morphol- of the paired helical fiament of Alzheimer disease. The partial ogy of the PHFs at the electron microscope level, and here amino acid sequence of this core protein was used to design we would accept only experiments on isolated individual synthetic oligonucleotide probes. The cDNA encodes a protein of filaments, not on neurofibrillary tangles (in which other 352 amino acids that contains a characteristic amino acid repeat material might be occluded). One thus needs a label or marker in its carboxyl-terminal half. This protein is highly homologous for the PHF itself, which can at the same time be used to to the sequence ofthe mouse microtubule-assoiated protein tau follow the steps of the biochemical purification.
    [Show full text]
  • Neurofilaments: Neurobiological Foundations for Biomarker Applications
    Neurofilaments: neurobiological foundations for biomarker applications Arie R. Gafson1, Nicolas R. Barthelmy2*, Pascale Bomont3*, Roxana O. Carare4*, Heather D. Durham5*, Jean-Pierre Julien6,7*, Jens Kuhle8*, David Leppert8*, Ralph A. Nixon9,10,11,12*, Roy Weller4*, Henrik Zetterberg13,14,15,16*, Paul M. Matthews1,17 1 Department of Brain Sciences, Imperial College, London, UK 2 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA 3 a ATIP-Avenir team, INM, INSERM , Montpellier university , Montpellier , France. 4 Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom 5 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada 6 Department of Psychiatry and Neuroscience, Laval University, Quebec, Canada. 7 CERVO Brain Research Center, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada 8 Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 9 Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA. 10Departments of Psychiatry, New York University School of Medicine, New York, NY, 10016, 11 Neuroscience Institute, New York University School of Medicine, New York, NY, 10016, USA. 12Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA 13 University College London Queen Square Institute of Neurology, London, UK 14 UK Dementia Research Institute at University College London 15 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 16 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 17 UK Dementia Research Institute at Imperial College, London * Co-authors ordered alphabetically Address for correspondence: Prof.
    [Show full text]