intermediate filament

File:Intermediate filament.svg

The structure of proteins that form intermediate filaments (IF) was first predicted by computerized analysis of the amino acid sequence of a human epidermal keratin derived from cloned cDNAs.{{cite journal | vauthors = Hanukoglu I, Fuchs E | title = The cDNA sequence of a human epidermal keratin: divergence of sequence but conservation of structure among intermediate filament proteins | journal = Cell | volume = 31 | issue = 1 | pages = 243–52 | date = November 1982 | pmid = 6186381 | doi = 10.1016/0092-8674(82)90424-X | url = https://zenodo.org/record/890743 | s2cid = 35796315 }} Analysis of a second keratin sequence revealed that the two types of keratins share only about 30% amino acid sequence homology but share similar patterns of secondary structure domains.{{cite journal | vauthors = Hanukoglu I, Fuchs E | title = The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins | journal = Cell | volume = 33 | issue = 3 | pages = 915–24 | date = July 1983 | pmid = 6191871 | doi = 10.1016/0092-8674(83)90034-X | url = https://zenodo.org/record/890739 | s2cid = 21490380 }} As suggested by the first model, all IF proteins appear to have a central alpha-helical rod domain that is composed of four alpha-helical segments (named as 1A, 1B, 2A and 2B) separated by three linker regions.{{cite journal | vauthors = Lee CH, Kim MS, Chung BM, Leahy DJ, Coulombe PA | title = Structural basis for heteromeric assembly and perinuclear organization of keratin filaments | journal = Nature Structural & Molecular Biology | volume = 19 | issue = 7 | pages = 707–15 | date = June 2012 | pmid = 22705788 | pmc = 3864793 | doi = 10.1038/nsmb.2330 }}

The central building block of an intermediate filament is a pair of two intertwined proteins that is called a coiled-coil structure. This name reflects the fact that the structure of each protein is helical, and the intertwined pair is also a helical structure. Structural analysis of a pair of keratins shows that the two proteins that form the coiled-coil bind by hydrophobic interactions.{{cite journal | vauthors = Hanukoglu I, Ezra L | title = Proteopedia entry: coiled-coil structure of keratins | journal = Biochemistry and Molecular Biology Education | volume = 42 | issue = 1 | pages = 93–4 | date = Jan 2014 | pmid = 24265184 | doi = 10.1002/bmb.20746 | s2cid = 30720797 | doi-access = free }}{{cite journal | vauthors = Qin Z, Kreplak L, Buehler MJ | title = Hierarchical structure controls nanomechanical properties of vimentin intermediate filaments | journal = PLOS ONE | volume = 4 | issue = 10 | pages = e7294 | date = October 2009 | pmid = 19806221 | pmc = 2752800 | doi = 10.1371/journal.pone.0007294 | bibcode = 2009PLoSO...4.7294Q | doi-access = free }} The charged residues in the central domain do not have a major role in the binding of the pair in the central domain.

Cytoplasmic IFs assemble into non-polar unit-length filaments (ULFs). Identical ULFs associate laterally into staggered, antiparallel, soluble tetramers, which associate head-to-tail into protofilaments that pair up laterally into protofibrils, four of which wind together into an intermediate filament.{{Cite book | vauthors=Lodish H, Berk A, Zipursky SL | url=https://archive.org/details/isbn_9780072930283/page/ | title=Molecular Cell Biology | year=2000 | publisher=W. H. Freeman | location=New York | isbn=978-0-07-243940-3 | page=[https://archive.org/details/isbn_9780072930283/page/ Section 19.6, Intermediate Filaments] | display-authors=etal | url-access=registration }}

Part of the assembly process includes a compaction step, in which ULF tighten and assume a smaller diameter. The reasons for this compaction are not well understood, and IF are routinely observed to have diameters ranging between 6 and 12 nm.{{cn|date=April 2025}}

The N-terminus and the C-terminus of IF proteins are non-alpha-helical regions and show wide variation in their lengths and sequences across IF families.

The N-terminal "head domain" binds DNA.{{cite journal | vauthors = Wang Q, Tolstonog GV, Shoeman R, Traub P | title = Sites of nucleic acid binding in type I-IV intermediate filament subunit proteins | journal = Biochemistry | volume = 40 | issue = 34 | pages = 10342–9 | date = August 2001 | pmid = 11513613 | doi = 10.1021/bi0108305 }} Vimentin heads are able to alter nuclear architecture and chromatin distribution, and the liberation of heads by HIV-1 protease may play an important role in HIV-1 associated cytopathogenesis and carcinogenesis.{{cite journal | vauthors = Shoeman RL, Hüttermann C, Hartig R, Traub P | title = Amino-terminal polypeptides of vimentin are responsible for the changes in nuclear architecture associated with human immunodeficiency virus type 1 protease activity in tissue culture cells | journal = Molecular Biology of the Cell | volume = 12 | issue = 1 | pages = 143–54 | date = January 2001 | pmid = 11160829 | pmc = 30574 | doi = 10.1091/mbc.12.1.143 }} Phosphorylation of the head region can affect filament stability.{{cite journal | vauthors = Takemura M, Gomi H, Colucci-Guyon E, Itohara S | title = Protective role of phosphorylation in turnover of glial fibrillary acidic protein in mice | journal = The Journal of Neuroscience | volume = 22 | issue = 16 | pages = 6972–9 | date = August 2002 | pmid = 12177195 | pmc = 6757867 | doi = 10.1523/JNEUROSCI.22-16-06972.2002 }} The head has been shown to interact with the rod domain of the same protein.{{cite journal | vauthors = Parry DA, Marekov LN, Steinert PM, Smith TA | title = A role for the 1A and L1 rod domain segments in head domain organization and function of intermediate filaments: structural analysis of trichocyte keratin | journal = Journal of Structural Biology | volume = 137 | issue = 1–2 | pages = 97–108 | year = 2002 | pmid = 12064937 | doi = 10.1006/jsbi.2002.4437 }}

C-terminal "tail domain" shows extreme length variation between different IF proteins.{{cite journal | vauthors = Quinlan R, Hutchison C, Lane B | title = Intermediate filament proteins | journal = Protein Profile | volume = 2 | issue = 8 | pages = 795–952 | year = 1995 | pmid = 8771189 }}

The anti-parallel orientation of tetramers means that, unlike microtubules and microfilaments, which have a plus end and a minus end, IFs lack polarity and cannot serve as basis for cell motility and intracellular transport.{{cn|date=April 2025}}

Also, unlike actin or tubulin, intermediate filaments do not contain a binding site for a nucleoside triphosphate.

Cytoplasmic IFs do not undergo treadmilling like microtubules and actin fibers, but are dynamic.{{cite journal | vauthors = Helfand BT, Chang L, Goldman RD | title = Intermediate filaments are dynamic and motile elements of cellular architecture | journal = Journal of Cell Science | volume = 117 | issue = Pt 2 | pages = 133–41 | date = January 2004 | pmid = 14676269 | doi = 10.1242/jcs.00936 | doi-access = free }}

IFs are rather deformable proteins that can be stretched several times their initial length.{{cite journal | vauthors = Herrmann H, Bär H, Kreplak L, Strelkov SV, Aebi U | title = Intermediate filaments: from cell architecture to nanomechanics | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 7 | pages = 562–73 | date = July 2007 | pmid = 17551517 | doi = 10.1038/nrm2197 | s2cid = 27115011 }}{{cite journal | vauthors = Qin Z, Kreplak L, Buehler MJ | title = Hierarchical structure controls nanomechanical properties of vimentin intermediate filaments | journal = PLOS ONE | volume = 4 | issue = 10 | pages = e7294 | date = October 2009 | pmid = 19806221 | pmc = 2752800 | doi = 10.1371/journal.pone.0007294 | bibcode = 2009PLoSO...4.7294Q | doi-access = free }}{{cite journal | vauthors = Kreplak L, Fudge D | title = Biomechanical properties of intermediate filaments: from tissues to single filaments and back | journal = BioEssays | volume = 29 | issue = 1 | pages = 26–35 | date = January 2007 | pmid = 17187357 | doi = 10.1002/bies.20514 | s2cid = 6560740 }}{{cite journal | vauthors = Qin Z, Buehler MJ, Kreplak L | title = A multi-scale approach to understand the mechanobiology of intermediate filaments | journal = Journal of Biomechanics | volume = 43 | issue = 1 | pages = 15–22 | date = January 2010 | pmid = 19811783 | doi = 10.1016/j.jbiomech.2009.09.004 }}{{cite journal | vauthors = Qin Z, Kreplak L, Buehler MJ | title = Nanomechanical properties of vimentin intermediate filament dimers | journal = Nanotechnology | volume = 20 | issue = 42 | page = 425101 | date = October 2009 | pmid = 19779230 | doi = 10.1088/0957-4484/20/42/425101 | bibcode = 2009Nanot..20P5101Q | s2cid = 6870454 }} The key to facilitate this large deformation is due to their hierarchical structure, which facilitates a cascaded activation of deformation mechanisms at different levels of strain. Initially the coupled alpha-helices of unit-length filaments uncoil as they're strained, then as the strain increases they transition into beta-sheets, and finally at increased strain the hydrogen bonds between beta-sheets slip and the ULF monomers slide along each other.

There are about 70 different human genes coding for various intermediate filament proteins. However, different kinds of IFs share basic characteristics: In general, they are all polymers that measure between 9–11 nm in diameter when fully assembled.{{cn|date=April 2025}}

Animal IFs are subcategorized into six types based on similarities in amino acid sequence and protein structure:

File:Epithelial-cells.jpg intermediate filaments (stained red) around epithelial cells]]

{{further|Cytokeratin}}

These proteins are the most diverse among IFs and constitute type I (acidic) and type II (basic) IF proteins. The many isoforms are divided in two groups:{{cn|date=April 2025}}

• epithelial keratins (about 20) in epithelial cells (image to right)
• trichocytic keratins (about 13) (hair keratins), which make up hair, nails, horns and reptilian scales.

Regardless of the group, keratins are either acidic or basic. Acidic and basic keratins bind each other to form acidic-basic heterodimers and these heterodimers then associate to make a keratin filament.

Cytokeratin filaments laterally associate with each other to create a thick bundle of ~50 nm radius. The optimal radius of such bundles is determined by the interplay between the long range electrostatic repulsion and short range hydrophobic attraction.{{cite journal | vauthors = Haimov E, Windoffer R, Leube RE, Urbakh M, Kozlov MM | title = Model for Bundling of Keratin Intermediate Filaments | journal = Biophysical Journal | volume = 119 | issue = 1 | pages = 65–74 | date = July 2020 | pmid = 32533940 | doi = 10.1016/j.bpj.2020.05.024 | pmc = 7335914 | bibcode = 2020BpJ...119...65H | doi-access = free }} Subsequently, these bundles would intersect through junctions to form a dynamic network, spanning the cytoplasm of epithelial cells.{{cn|date=April 2025}}

File:Vimentin.jpg fibers in fibroblasts]]

There are four proteins classed as type III intermediate filament proteins, which may form homo- or heteropolymeric proteins.

• Desmin IFs are structural components of the sarcomeres in muscle cells and connect different cell organelles like the desmosomes with the cytoskeleton.{{cite journal | vauthors = Brodehl A, Gaertner-Rommel A, Milting H | title = Molecular insights into cardiomyopathies associated with desmin (DES) mutations | journal = Biophysical Reviews | volume = 10 | issue = 4 | pages = 983–1006 | date = August 2018 | pmid = 29926427 | pmc = 6082305 | doi = 10.1007/s12551-018-0429-0 }}
• Glial fibrillary acidic protein (GFAP) is found in astrocytes and other glia.{{cn|date=April 2025}}
• Peripherin found in peripheral neurons.{{cn|date=April 2025}}
• Vimentin, the most widely distributed of all IF proteins, can be found in fibroblasts, leukocytes, and blood vessel endothelial cells. They support the cellular membranes, keep some organelles in a fixed place within the cytoplasm, and transmit membrane receptor signals to the nucleus.
• Syncoilin is an atypical type III IF protein.{{cite web |title=SYNC – Syncoilin – Homo sapiens (Human) – SYNC gene & protein |url=https://www.uniprot.org/uniprot/Q9H7C4 |website=www.uniprot.org |access-date=20 December 2021 |language=en}}

• Alpha-internexin
• Neurofilaments – the type IV family of intermediate filaments that is found in high concentrations along the axons of vertebrate neurons.{{cn|date=April 2025}}
• Synemin
• Syncoilin

• Lamins

Lamins are fibrous proteins having structural function in the cell nucleus.{{cn|date=April 2025}}

In metazoan cells, there are A and B type lamins, which differ in their length and pI. Human cells have three differentially regulated genes.

B-type lamins are present in every cell. B type lamins, lamin B1 and B2, are expressed from the LMNB1 and LMNB2 genes on 5q23 and 19q13, respectively.

A-type lamins are only expressed following gastrulation. Lamin A and C are the most common A-type lamins and are splice variants of the LMNA gene found at 1q21.{{cn|date=April 2025}}

These proteins localize to two regions of the nuclear compartment, the nuclear lamina—a proteinaceous structure layer subjacent to the inner surface of the nuclear envelope and throughout the nucleoplasm in the nucleoplasmic veil.

Comparison of the lamins to vertebrate cytoskeletal IFs shows that lamins have an extra 42 residues (six heptads) within coil 1b. The c-terminal tail domain contains a nuclear localization signal (NLS), an Ig-fold-like domain, and in most cases a carboxy-terminal CaaX box that is isoprenylated and carboxymethylated (lamin C does not have a CAAX box). Lamin A is further processed to remove the last 15 amino acids and its farnesylated cysteine.

During mitosis, lamins are phosphorylated by MPF, which drives the disassembly of the lamina and the nuclear envelope.

• Beaded filaments: Filensin, Phakinin.
• Nestin (was once proposed for reclassification but due to differences, remains as a type VI IF protein){{cite journal | vauthors = Bernal A, Arranz L | title = Nestin-expressing progenitor cells: function, identity and therapeutic implications | journal = Cellular and Molecular Life Sciences | volume = 75 | issue = 12 | pages = 2177–2195 | date = June 2018 | pmid = 29541793 | pmc = 5948302 | doi = 10.1007/s00018-018-2794-z}}

Vertebrate-only. Related to type I-IV. Used to contain other newly discovered IF proteins not yet assigned to a type.

At the plasma membrane, some keratins or desmin interact with desmosomes (cell-cell adhesion) and hemidesmosomes (cell-matrix adhesion) via adapter proteins.{{cn|date=April 2025}}

Filaggrin binds to keratin fibers in epidermal cells. Plectin links vimentin to other vimentin fibers, as well as to microfilaments, microtubules, and myosin II. Kinesin is being researched and is suggested to connect vimentin to tubulin via motor proteins.

Keratin filaments in epithelial cells link to desmosomes (desmosomes connect the cytoskeleton together) through plakoglobin, desmoplakin, desmogleins, and desmocollins; desmin filaments are connected in a similar way in heart muscle cells.

• Dilated cardiomyoathy (DCM), mutations in the DES gene{{cite journal | vauthors = Fischer B, Dittmann S, Brodehl A, Unger A, Stallmeyer B, Paul M, Seebohm G, Kayser A, Peischard S, Linke WA, Milting H, Schulze-Bahr E | display-authors = 6 | title = Functional characterization of novel alpha-helical rod domain desmin (DES) pathogenic variants associated with dilated cardiomyopathy, atrioventricular block and a risk for sudden cardiac death | journal = International Journal of Cardiology | pages = 167–174 | date = December 2020 | volume = 329 | pmid = 33373648 | doi = 10.1016/j.ijcard.2020.12.050 | s2cid = 229719883 }}
• Arrhythmogenic cardiomyopathy (ACM), mutations in the DES gene{{cite journal | vauthors = Bermúdez-Jiménez FJ, Carriel V, Brodehl A, Alaminos M, Campos A, Schirmer I, Milting H, Abril BÁ, Álvarez M, López-Fernández S, García-Giustiniani D, Monserrat L, Tercedor L, Jiménez-Jáimez J | display-authors = 6 | title = Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia | journal = Circulation | volume = 137 | issue = 15 | pages = 1595–1610 | date = April 2018 | pmid = 29212896 | doi = 10.1161/CIRCULATIONAHA.117.028719 | s2cid = 4715358 | doi-access = free | hdl = 10481/89514 | hdl-access = free }}{{cite journal | vauthors = Protonotarios A, Brodehl A, Asimaki A, Jager J, Quinn E, Stanasiuk C, Ratnavadivel S, Futema M, Akhtar MM, Gossios TD, Ashworth M, Savvatis K, Walhorn V, Anselmetti D, Elliott PM, Syrris P, Milting H, Lopes LR | display-authors = 6 | title = The novel desmin variant p.Leu115Ile is associated with a unique form of biventricular Arrhythmogenic Cardiomyopathy | journal = The Canadian Journal of Cardiology | pages = 857–866 | date = December 2020 | volume = 37 | issue = 6 | pmid = 33290826 | doi = 10.1016/j.cjca.2020.11.017 | s2cid = 228078648 | url = https://discovery.ucl.ac.uk/id/eprint/10117120/ }}{{cite journal | vauthors = Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H | display-authors = 6 | title = De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy | journal = Human Molecular Genetics | volume = 19 | issue = 23 | pages = 4595–607 | date = December 2010 | pmid = 20829228 | doi = 10.1093/hmg/ddq387 | doi-access = free }}{{cite journal | vauthors = Brodehl A, Hedde PN, Dieding M, Fatima A, Walhorn V, Gayda S, Šarić T, Klauke B, Gummert J, Anselmetti D, Heilemann M, Nienhaus GU, Milting H | display-authors = 6 | title = Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants | journal = The Journal of Biological Chemistry | volume = 287 | issue = 19 | pages = 16047–57 | date = May 2012 | pmid = 22403400 | pmc = 3346104 | doi = 10.1074/jbc.M111.313841 | doi-access = free }}
• Restrictive cardiomyopathy (RCM), mutations in the DES gene{{cite journal | vauthors = Brodehl A, Pour Hakimi SA, Stanasiuk C, Ratnavadivel S, Hendig D, Gaertner A, Gerull B, Gummert J, Paluszkiewicz L, Milting H | display-authors = 6 | title = Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect | journal = Genes | volume = 10 | issue = 11 | page = 918 | date = November 2019 | pmid = 31718026 | pmc = 6896098 | doi = 10.3390/genes10110918 | doi-access = free }}
• Non-compaction cardiomyopathy, mutations in the DES genes{{cite journal | vauthors = Kley RA, Hellenbroich Y, van der Ven PF, Fürst DO, Huebner A, Bruchertseifer V, Peters SA, Heyer CM, Kirschner J, Schröder R, Fischer D, Müller K, Tolksdorf K, Eger K, Germing A, Brodherr T, Reum C, Walter MC, Lochmüller H, Ketelsen UP, Vorgerd M | display-authors = 6 | title = Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients | journal = Brain: A Journal of Neurology| volume = 130 | issue = Pt 12 | pages = 3250–64 | date = December 2007 | pmid = 18055494 | doi = 10.1093/brain/awm271| doi-access = free }}{{cite journal | vauthors = Marakhonov AV, Brodehl A, Myasnikov RP, Sparber PA, Kiseleva AV, Kulikova OV, Meshkov AN, Zharikova AA, Koretsky SN, Kharlap MS, Stanasiuk C, Mershina EA, Sinitsyn VE, Shevchenko AO, Mozheyko NP, Drapkina OM, Boytsov SA, Milting H, Skoblov MY | display-authors = 6 | title = Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect | journal = Human Mutation | volume = 40 | issue = 6 | pages = 734–741 | date = June 2019 | pmid = 30908796 | doi = 10.1002/humu.23747 | s2cid = 85515283 | doi-access = free }}
• Cardiomyopathy in combination with skeletal myopathy (DES){{cite journal | vauthors = Schirmer I, Dieding M, Klauke B, Brodehl A, Gaertner-Rommel A, Walhorn V, Gummert J, Schulz U, Paluszkiewicz L, Anselmetti D, Milting H | display-authors = 6 | title = A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy | journal = Molecular Genetics & Genomic Medicine | volume = 6 | issue = 2 | pages = 288–293 | date = March 2018 | pmid = 29274115 | pmc = 5902401 | doi = 10.1002/mgg3.358 }}
• Epidermolysis bullosa simplex; keratin 5 or keratin 14 mutation
• Laminopathies are a family of diseases caused by mutations in nuclear lamins and include Hutchinson-Gilford progeria syndrome and various lipodystrophies and cardiomyopathies among others.

IF proteins are universal among animals in the form of a nuclear lamin. The Hydra has an additional "nematocilin" derived from the lamin. Cytoplasmic IFs (type I-IV) are only found in Bilateria; they also arose from a gene duplication event involving "type V" nuclear lamin. In addition, a few other diverse types of eukaryotes have lamins, suggesting an early origin of the protein.{{cite journal | vauthors = Kollmar M | title = Polyphyly of nuclear lamin genes indicates an early eukaryotic origin of the metazoan-type intermediate filament proteins | journal = Scientific Reports | volume = 5 | page = 10652 | date = May 2015 | pmid = 26024016 | pmc = 4448529 | doi = 10.1038/srep10652 | doi-access = free | bibcode = 2015NatSR...510652K }}

There was not really a concrete definition of an "intermediate filament protein", in the sense that the size or shape-based definition does not cover a monophyletic group. With the inclusion of unusual proteins like the network-forming beaded lamins (type VI), the current classification is moving to a clade containing nuclear lamin and its many descendants, characterized by sequence similarity as well as the exon structure. Functionally-similar proteins out of this clade, like crescentins, alveolins, tetrins, and epiplasmins, are therefore only "IF-like". They likely arose through convergent evolution.

{{reflist|2}}

{{refbegin}}

• {{cite book | veditors = Herrmann H, Harris JR | title = Intermediate filaments | publisher = Springer | year = 1998 | isbn = 978-0-306-45854-5 | url = https://books.google.com/books?id=DjYdWQl_McQC }}
• {{cite book | veditors = Omary MB, Coulombe PA | title = Intermediate filament cytoskeleton | publisher = Gulf Professional Publishing | year = 2004 | isbn = 978-0-12-564173-9 | url = https://books.google.com/books?id=2vXL7DQgQAUC }}
• {{cite book | veditors = Paramio JM | title = Intermediate filaments | publisher = Springer | year = 2006 | isbn = 978-0-387-33780-7 | url = https://books.google.com/books?id=XpAM-5jQ42oC }}

{{refend}}

{{Commons category|Intermediate filament protein, coiled coil region}}

• {{MeshName|Intermediate+Filament+Proteins}}

{{Cytoskeletal Proteins}}

{{Organelles}}

{{InterPro content|IPR001322}}

{{InterPro content|IPR006821}}

{{DEFAULTSORT:Intermediate Filament}}

Category:Protein families

Category:Cytoskeleton