Summary: Intermediate filament head (DNA binding) region
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Intermediate filament Edit Wikipedia article
|Intermediate filament tail domain|
structure of lamin a/c globular domain
|SCOPe||1ivt / SUPFAM|
|Intermediate filament rod domain|
human vimentin coil 2b fragment (cys2)
|SCOPe||1gk7 / SUPFAM|
|Intermediate filament head (DNA binding) region|
|SCOPe||1gk7 / SUPFAM|
|Peripherin neuronal intermediate filament protein|
|Locus||Chr. 12 q13.12|
|Nestin neuronal stem cell intermediate filament protein|
|Locus||Chr. 1 q23.1|
Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate Branchiostoma.
Intermediate filaments are composed of a family of related proteins sharing common structural and sequence features. Initially designated 'intermediate' because their average diameter (10 nm) is between those of narrower microfilaments (actin) and wider myosin filaments found in muscle cells, the diameter of intermediate filaments is now commonly compared to actin microfilaments (7 nm) and microtubules (25 nm). Intermediate filaments are subcategorized into six types based on similarities in amino acid sequence and protein structure. Most types are cytoplasmic, but one type, Type V is a nuclear lamin. Unlike microtubules, IF distribution in cells show no good correlation with the distribution of either mitochondria or endoplasmic reticulum.
- 1 Structure
- 2 Biomechanical properties
- 3 Types
- 4 Cell adhesion
- 5 Associated proteins
- 6 Diseases arising from mutations in IF genes
- 7 References
- 8 Further reading
- 9 External links
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. 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. 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.
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. 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. 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.
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. 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. Phosphorylation of the head region can affect filament stability. The head has been shown to interact with the rod domain of the same protein.
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.
IFs are rather deformable proteins that can be stretched several times their initial length. 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 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.
Types I and II â€“ acidic and basic keratins
- 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.
- Desmin IFs are structural components of the sarcomeres in muscle cells.
- GFAP (glial fibrillary acidic protein) is found in astrocytes and other glia.
- Peripherin found in peripheral neurons.
- 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.
- Neurofilaments - the type IV family of intermediate filaments that is found in high concentrations along the axons of vertebrate neurons.
Type V - nuclear lamins
Lamins are fibrous proteins having structural function in the cell nucleus.
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.
These proteins localize to two regions of the nuclear compartment, the nuclear laminaâ€”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.
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.
Diseases arising from mutations in IF genes
- Arrhythmogenic cardiomyopathy (ACM), mutations in the DES gene.
- 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.
- Herrmann H, BÃ¤r H, Kreplak L, Strelkov SV, Aebi U (July 2007). "Intermediate filaments: from cell architecture to nanomechanics". Nature Reviews. Molecular Cell Biology. 8 (7): 562â€“73. doi:10.1038/nrm2197. PMID 17551517.
- Chang L, Goldman RD (August 2004). "Intermediate filaments mediate cytoskeletal crosstalk". Nature Reviews. Molecular Cell Biology. 5 (8): 601â€“13. doi:10.1038/nrm1438. PMID 15366704.
- Traub, P. (2012), Intermediate Filaments: A Review, Springer Berlin Heidelberg, p. 33, ISBN 9783642702303CS1 maint: uses authors parameter (link)
- Karabinos A, Riemer D, Erber A, Weber K (October 1998). "Homologues of vertebrate type I, II and III intermediate filament (IF) proteins in an invertebrate: the IF multigene family of the cephalochordate Branchiostoma". FEBS Letters. 437 (1â€“2): 15â€“8. doi:10.1016/S0014-5793(98)01190-9. PMID 9804163.
- Ishikawa H, Bischoff R, Holtzer H (September 1968). "Mitosis and intermediate-sized filaments in developing skeletal muscle". J. Cell Biol. 38 (3): 538â€“55. doi:10.1083/jcb.38.3.538. PMC 2108373. PMID 5664223.
- "Human Intermediate Filament Database". www.interfil.org.
- Soltys, BJ and Gupta RS: Interrelationships of endoplasmic reticulum, mitochondria, intermediate filaments, and microtubules-a quadruple fluorescence labeling study. Biochem. Cell. Biol. (1992) 70: 1174-1186
- Hanukoglu I, Fuchs E (November 1982). "The cDNA sequence of a human epidermal keratin: divergence of sequence but conservation of structure among intermediate filament proteins". Cell. 31 (1): 243â€“52. doi:10.1016/0092-8674(82)90424-X. PMID 6186381.
- Hanukoglu I, Fuchs E (July 1983). "The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins". Cell. 33 (3): 915â€“24. doi:10.1016/0092-8674(83)90034-X. PMID 6191871.
- Lee CH, Kim MS, Chung BM, Leahy DJ, Coulombe PA (July 2012). "Structural basis for heteromeric assembly and perinuclear organization of keratin filaments". Nat. Struct. Mol. Biol. 19 (7): 707â€“15. doi:10.1038/nsmb.2330. PMC 3864793. PMID 22705788.
- Hanukoglu I, Ezra L (Jan 2014). "Proteopedia: Coiled-coil structure of keratins". Biochem Mol Biol Educ. 42 (1): 93â€“94. doi:10.1002/bmb.20746. PMID 24265184.
- Qin Z, Kreplak L, Buehler MJ (2009). "Hierarchical structure controls nanomechanical properties of vimentin intermediate filaments". PLoS ONE. 4 (10): e7294. Bibcode:2009PLoSO...4.7294Q. doi:10.1371/journal.pone.0007294. PMC 2752800. PMID 19806221.
- Lodish H, Berk A, Zipursky SL, et al. (2000). Molecular Cell Biology. New York: W. H. Freeman. p. Section 19.6, Intermediate Filaments. ISBN 978-0-07-243940-3.
- Wang Q, Tolstonog GV, Shoeman R, Traub P (August 2001). "Sites of nucleic acid binding in type I-IV intermediate filament subunit proteins". Biochemistry. 40 (34): 10342â€“9. doi:10.1021/bi0108305. PMID 11513613.
- Shoeman RL, Huttermann C, Hartig R, Traub P (January 2001). "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". Mol. Biol. Cell. 12 (1): 143â€“54. doi:10.1091/mbc.12.1.143. PMC 30574. PMID 11160829.
- Takemura M, Gomi H, Colucci-Guyon E, Itohara S (August 2002). "Protective role of phosphorylation in turnover of glial fibrillary acidic protein in mice". J. Neurosci. 22 (16): 6972â€“9. doi:10.1523/JNEUROSCI.22-16-06972.2002. PMC 6757867. PMID 12177195.
- Parry DA, Marekov LN, Steinert PM, Smith TA (2002). "A role for the 1A and L1 rod domain segments in head domain organization and function of intermediate filaments: structural analysis of trichocyte keratin". J. Struct. Biol. 137 (1â€“2): 97â€“108. doi:10.1006/jsbi.2002.4437. PMID 12064937.
- Quinlan R, Hutchison C, Lane B (1995). "Intermediate filament proteins". Protein Profile. 2 (8): 795â€“952. PMID 8771189.
- Helfand, Brian T.; Chang, Lynne; Goldman, Robert D. (15 January 2004). "Intermediate filaments are dynamic and motile elements of cellular architecture". Journal of Cell Science. 117 (2): 133â€“141. doi:10.1242/jcs.00936. PMID 14676269. Retrieved 8 December 2019.
- Herrmann H, BÃ¤r H, Kreplak L, Strelkov SV, Aebi U (July 2007). "Intermediate filaments: from cell architecture to nanomechanics". Nat. Rev. Mol. Cell Biol. 8 (7): 562â€“73. doi:10.1038/nrm2197. PMID 17551517.Qin Z, Kreplak L, Buehler MJ (2009). "Hierarchical structure controls nanomechanical properties of vimentin intermediate filaments". PLoS ONE. 4 (10): e7294. Bibcode:2009PLoSO...4.7294Q. doi:10.1371/journal.pone.0007294. PMC 2752800. PMID 19806221.Kreplak L, Fudge D (January 2007). "Biomechanical properties of intermediate filaments: from tissues to single filaments and back". BioEssays. 29 (1): 26â€“35. doi:10.1002/bies.20514. PMID 17187357.Qin Z, Buehler MJ, Kreplak L (January 2010). "A multi-scale approach to understand the mechanobiology of intermediate filaments". J Biomech. 43 (1): 15â€“22. doi:10.1016/j.jbiomech.2009.09.004. PMID 19811783.Qin Z, Kreplak L, Buehler MJ (October 2009). "Nanomechanical properties of vimentin intermediate filament dimers". Nanotechnology. 20 (42): 425101. Bibcode:2009Nanot..20P5101Q. doi:10.1088/0957-4484/20/42/425101. PMID 19779230.
- Steinert PM, Chou YH, Prahlad V, Parry DA, Marekov LN, Wu KC, Jang SI, Goldman RD (April 1999). "A high molecular weight intermediate filament-associated protein in BHK-21 cells is nestin, a type VI intermediate filament protein. Limited co-assembly in vitro to form heteropolymers with type III vimentin and type IV alpha-internexin". J. Biol. Chem. 274 (14): 9881â€“90. doi:10.1074/jbc.274.14.9881. PMID 10092680.
- 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 (December 2010). "De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy". Hum. Mol. Genet. 19 (23): 4595â€“607. doi:10.1093/hmg/ddq387. PMID 20829228.
- Brodehl A, Hedde PN, Dieding M, Fatima A, Walhorn V, Gayda S, Å ariÄ‡ T, Klauke B, Gummert J, Anselmetti D, Heilemann M, Nienhaus GU, Milting H (May 2012). "Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants". J. Biol. Chem. 287 (19): 16047â€“57. doi:10.1074/jbc.M111.313841. PMC 3346104. PMID 22403400.
- Herrmann H, Harris JR, eds. (1998). Intermediate filaments. Springer. ISBN 978-0-306-45854-5.
- Omary MB, Coulombe PA, eds. (2004). Intermediate filament cytoskeleton. Gulf Professional Publishing. ISBN 978-0-12-564173-9.
- Paramio JM, ed. (2006). Intermediate filaments. Springer. ISBN 978-0-387-33780-7.
|Wikimedia Commons has media related to Intermediate filament protein, coiled coil region.|
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Intermediate filament head (DNA binding) region Provide feedback
This family represents the N-terminal head region of intermediate filaments. Intermediate filament heads bind DNA . Vimentin heads are able to alter nuclear architecture and chromatin distribution, and the liberation of heads by HIV-1 protease liberates may play an important role in HIV-1 associated cytopathogenesis and carcinogenesis . Phosphorylation of the head region can affect filament stability . The head has been shown to interaction with the rod domain of the same protein .
Shoeman RL, Huttermann C, Hartig R, Traub P; , Mol Biol Cell 2001;12:143-154.: 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. PUBMED:11160829 EPMC:11160829
Takemura M, Gomi H, Colucci-Guyon E, Itohara S; , J Neurosci 2002;22:6972-6979.: Protective role of phosphorylation in turnover of glial fibrillary acidic protein in mice. PUBMED:12177195 EPMC:12177195
Parry DA, Marekov LN, Steinert PM, Smith TA; , J Struct Biol 2002;137:97-108.: A Role for the 1A and L1 Rod Domain Segments in Head Domain Organization and Function of Intermediate Filaments: Structural Analysis of Trichocyte Keratin. PUBMED:12064937 EPMC:12064937
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR006821
This entry represents the N-terminal head domain of intermediate filaments. Intermediate filament heads bind DNA [PUBMED:11513613]. Vimentin heads are able to alter nuclear architecture and chromatin distribution, and the liberation of heads by HIV-1 protease liberates may play an important role in HIV-1 associated cytopathogenesis and carcinogenesis [PUBMED:11160829]. Phosphorylation of the head region can affect filament stability [PUBMED:12177195]. The head has been shown to interaction with the rod domain of the same protein [PUBMED:12064937].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||intermediate filament (GO:0005882)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Number in seed:||45|
|Number in full:||1514|
|Average length of the domain:||83.30 aa|
|Average identity of full alignment:||28 %|
|Average coverage of the sequence by the domain:||16.35 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
|Download:||download the raw HMM for this family|
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The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Filament_head domain has been found. There are 12 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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