Keratins

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Crystal structure of the 2B helical domain of coiled-coil dimer of K5-K14 keratins (residues Thr382-Gly476 of K5 and Ser332-Gly421 of K14). PDB ID: 3TNU.

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Keratin is the name given to a large family of homologous proteins that have a filamentous (fibrous) structure. These proteins are expressed in epithelial cells and in epidermal cells where they they are assembled forming cytoskeletal structures within the cell and epidermal derivatives such as hair, nail and horn [1].

The keratins represent the largest branch within the super-family of intermediate-filament (IF) proteins [2] [3]. Keratins are grouped into two families termed as type I and type II keratins based on their sequence homology [4]. Similarly, other IF proteins are also grouped into families termed consecutively as types III, IV, V and VI IF proteins, based on their sequence homology [5]. These families include desmin, vimentin, neurofilament protein and GFAP that are expressed in specific tissues and cell types [2]. The IF family of lamins are located on the nuclear lamina and are ubiquitously expressed [2].

Intermediate filamentsIntermediate filaments

In most eukaryotic cells there are three major cytoskeletal systems: [6]

  • Microfilaments composed of actin subunits
  • Intermediate filaments
  • Microtubules composed of tubulin subunits

The name "intermediate filament" reflects the comparative morphology of these filaments as their diameter is about 8-12 nm; a value that is "intermediate" between microfilaments with a diameter of 6-7 nm and microtubules with a diameter of 25 nm [7].

Both microfilaments and microtubules are assembled from globular subunits of actin and tubulin respectively. In contrast, intermediate filaments (IFs) are composed of proteins that have a long fibrous structure that results from long stretches of alpha helical domains.

The basic building block of each intermediate filament is a dimer of a coiled-coil pair of IF proteins. Each keratin filament is assembled as a hetero-dimer of a type I keratin coiled together with a type II keratin. [4]. Other types of IFs are mostly composed of homo-dimers [2].

Primary structures of keratinsPrimary structures of keratins

In humans there are 54 functional genes that code for keratins [8] [9]. The first sequences of human keratin cDNAs revealed that there are two distinct but homologous keratin families [10] [4]. These two distinct types were named as Type I keratin and Type II keratin [4].

Human genome sequencing revealed that type I and type II keratin genes are located in two clusters each of which includes 27 genes on chromosome 17q21 and on chromosome 12q13 respectively [9] [11]. The juxtaposed location of the genes indicate that these gene clusters evolved by a series of gene duplication events.

Determination of the sequences of type I and type keratins revealed that the two types of keratins have a central ~300 residue long segment that show ~30% homology, but the amino and carboxy terminal regions of these proteins show great diversity [10]. Consistent with the initial observations, sequencing of keratins and other intermediate filament proteins showed that all IF proteins have a conserved central domain and widely divergent amino and carboxy terminal regions [12].

Sequencing and two dimensional gel electrophoresis of the complete family of keratins revealed that the type I and type II keratins differ in their size and isolelectric points [13] [14]. Type I keratins are generally smaller (average length 460 aa's), and acidic (isoelectric point 4.4-5.4), while type II keratins are longer (average length 545 aa's) and basic (isoelectric point 5-8.3). As noted, the size differences among keratins result from differences in the amino and carboxy terminals of the proteins [4].

Secondary structures of keratinsSecondary structures of keratins

The first model of alpha-helix was proposed by Pauling based on the crystallography of wool fibers [15] that were shown to have long helical segments [16].

Analysis of the first cytoskeletal keratin sequence revealed that this protein contains a central domain of ~300 residues that was predicted to be mostly in alpha helix conformation [10]. By comparative analysis of the predicted structures of a type I keratin, a type II keratin, desmin and vimentin, Hanukoglu and Fuchs suggested that all IF proteins have a central ~300 residue domain that contains four segments in alpha helical conformation that are separated by three short linker segments predicted to be in beta-turn conformation [4]. This model has been confirmed by analysis of the crystal structure of segments of keratin coiled-coil [17].


Tertiary and quaternary structures of keratinsTertiary and quaternary structures of keratins

ReferencesReferences

  1. ↑ Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008 Jun;129(6):705-33. doi: 10.1007/s00418-008-0435-6. Epub, 2008 May 7. PMID:18461349 doi:10.1007/s00418-008-0435-6
  2. ↑ 2.0 2.1 2.2 2.3 Godsel LM, Hobbs RP, Green KJ. Intermediate filament assembly: dynamics to disease. Trends Cell Biol. 2008 Jan;18(1):28-37. PMID:18083519 doi:10.1016/j.tcb.2007.11.004
  3. ↑ Eriksson JE, Dechat T, Grin B, Helfand B, Mendez M, Pallari HM, Goldman RD. Introducing intermediate filaments: from discovery to disease. J Clin Invest. 2009 Jul;119(7):1763-71. doi: 10.1172/JCI38339. Epub 2009 Jul 1. PMID:19587451 doi:10.1172/JCI38339
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Hanukoglu I, Fuchs E. The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins. Cell. 1983 Jul;33(3):915-24. PMID:6191871
  5. ↑ Fuchs E. The cytoskeleton and disease: genetic disorders of intermediate filaments. Annu Rev Genet. 1996;30:197-231. PMID:8982454 doi:10.1146/annurev.genet.30.1.197
  6. ↑ Suozzi KC, Wu X, Fuchs E. Spectraplakins: master orchestrators of cytoskeletal dynamics. J Cell Biol. 2012 May 14;197(4):465-75. doi: 10.1083/jcb.201112034. PMID:22584905 doi:10.1083/jcb.201112034
  7. ↑ Wade RH. On and around microtubules: an overview. Mol Biotechnol. 2009 Oct;43(2):177-91. doi: 10.1007/s12033-009-9193-5. Epub 2009 , Jun 30. PMID:19565362 doi:10.1007/s12033-009-9193-5
  8. ↑ Schweizer J, Bowden PE, Coulombe PA, Langbein L, Lane EB, Magin TM, Maltais L, Omary MB, Parry DA, Rogers MA, Wright MW. New consensus nomenclature for mammalian keratins. J Cell Biol. 2006 Jul 17;174(2):169-74. Epub 2006 Jul 10. PMID:16831889 doi:10.1083/jcb.200603161
  9. ↑ 9.0 9.1 Hesse M, Zimek A, Weber K, Magin TM. Comprehensive analysis of keratin gene clusters in humans and rodents. Eur J Cell Biol. 2004 Feb;83(1):19-26. PMID:15085952
  10. ↑ 10.0 10.1 10.2 Hanukoglu I, Fuchs E. The cDNA sequence of a human epidermal keratin: divergence of sequence but conservation of structure among intermediate filament proteins. Cell. 1982 Nov;31(1):243-52. PMID:6186381
  11. ↑ Schweizer J, Langbein L, Rogers MA, Winter H. Hair follicle-specific keratins and their diseases. Exp Cell Res. 2007 Jun 10;313(10):2010-20. Epub 2007 Mar 14. PMID:17428470 doi:10.1016/j.yexcr.2007.02.032
  12. ↑ Parry DA, Strelkov SV, Burkhard P, Aebi U, Herrmann H. Towards a molecular description of intermediate filament structure and assembly. Exp Cell Res. 2007 Jun 10;313(10):2204-16. Epub 2007 Apr 12. PMID:17521629 doi:10.1016/j.yexcr.2007.04.009
  13. ↑ Bragulla HH, Homberger DG. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia. J Anat. 2009 Apr;214(4):516-59. PMID:19422428 doi:JOA1066
  14. ↑ Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008 Jun;129(6):705-33. doi: 10.1007/s00418-008-0435-6. Epub, 2008 May 7. PMID:18461349 doi:10.1007/s00418-008-0435-6
  15. ↑ Eisenberg D. The discovery of the alpha-helix and beta-sheet, the principal structural features of proteins. Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11207-10. Epub 2003 Sep 9. PMID:12966187 doi:http://dx.doi.org/10.1073/pnas.2034522100
  16. ↑ Crewther WG, Harrap BS. The preparation and properties of a helix-rich fraction obtained by partial proteolysis of low sulfur S-carboxymethylkerateine from wool. J Biol Chem. 1967 Oct 10;242(19):4310-9. PMID:6072928
  17. ↑ Coulombe PA, Bousquet O, Ma L, Yamada S, Wirtz D. The 'ins' and 'outs' of intermediate filament organization. Trends Cell Biol. 2000 Oct;10(10):420-8. PMID:10998598

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Israel Hanukoglu, Liora Ezra, Michal Harel, Angel Herraez
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