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Inner nuclear membrane protein

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Inner nuclear membrane proteins structure. Amino-termini (N) and carboxy-termini (C) are indicated in red. Adapted from Holmer and Worman (2001)[1]

Inner nuclear membrane (INM) proteins are proteins that are embedded in or associated with the inner membrane of the nuclear envelope (NE). There are about 60 INM proteins, most of which are poorly characterized with respect to structure and function.[2] Among the few well-characterized INM proteins are lamin B receptor (LBR), the lamina-associated polypeptide 1 (LAP1), the lamina-associated polypeptide-2 (LAP2), emerin and MAN1. All INM proteins are arranged such that their N-termini is facing the nucleoplasm and targeted by various kinases.[3]

Common structural features

There have been identified several integral nuclear membrane proteins of different size and structure.[4] It is proposed that they share some structural features with respect to nucleoplasmic domain(s) and lipid soluble domain(s). Some INM proteins contain common protein domain structures, and can thus be categorised into known protein domain families. These include the LEM-, SUN-, and KASH-domain families. Members of the LEM-domain family play a part in chromatin organisation. SUN- and KASH-domains participate in linking the cytoskeleton and nucleoskeleton through the LINC complex.[5]

Function

Lamins and chromatin found at the nuclear envelope are organised with the assistance of proteins embedded in the INM.[6] INM proteins also aid in organization of nuclear pore complexes (NPCs). The protein mPom121 is targeted to the INM and is necessary for NPC formation.[4] Proteins containing the LEM domain, such as emerin, LAP2β and MAN1, interact with the barrier-to-autointegration factor (BAF).[7]

Synthesis and translocation

INM proteins are synthesized in one of three places; in the cytoplasm, the cytoplasmic ER, or the outer nuclear membrane (ONM). All require localisation to the INM.[5] Since the outer nuclear membrane is continuous with the endoplasmic reticulum it is possible that the inner nuclear membrane proteins are translated on the rough endoplasmic reticulum, whereby the proteins move into the nucleus by lateral diffusion through a nuclear pore.[4] In this model, proteins diffuse freely from the ER to the inner nuclear membrane, where association with nuclear lamina or chromatin immobilizes them. [8] Current opinion is that INM proteins synthesised in the cytoplasm are transported to the INM through nuclear pore complexes (NPC).[5] There are several proteins associated with the inner nuclear membrane. It is likely that the majority of them are also associated with the nuclear lamina. Some may interact directly with the nuclear lamina, and some may be associated with it through scaffold proteins.[4]

Examples of inner nuclear membrane proteins

Inner nuclear membrane proteins and disease

Mutations in the gene EDM, encoding the INM protein emerin may be the cause of X-linked Emery-Dreifuss muscular dystrophy.[2] As mutations in lamins cause the autosomal dominant form of Emery-Dreifuss muscular dystrophy, and lamins and emerin are known to interact, it has been hypothesised that muscle disease may be caused by a structural defect in the NE brought on by dysfunction in one of these proteins.[1] The wide array of diseases involving lamins and their associated inner nuclear membrane proteins are collectively called laminopathies.[9]

Tumor cells often show an abherent structure of the nucleus, and is used by pathologists in diagnostics . As changes in the nuclear envelope correspond to functional changes in the nucleus, morphological changes in the nucleus may be involved in carcinogenesis. The regulatory functions of inner nuclear membrane proteins strongly suggest this possibility. [10] Mutations in the gene LBR, encoding lamin B receptor, causes Pelger-Hüet anomaly.[11]

See also

References

  1. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11766875, please use {{cite journal}} with |pmid=11766875 instead.
  2. ^ a b Iván Méndez-López and Howard J. Worman (2012) Inner nuclear membrane proteins: impact on human disease. Chromosoma Apr;121(2):153-67 PMID 22307332 Cite error: The named reference "Lopez" was defined multiple times with different content (see the help page).
  3. ^ Georgatos SD (2001) The inner nuclear membrane: simple, or very complex? EMBO J. 20(12):2989-94 PMID 11406575
  4. ^ a b c d Senior, A and Gerace, L 1988, ’Integral membrane proteins specific to the inner nuclear membrane associated with the nuclear lamina’, The Journal of Cell Biology, vol. 107, no. 6, pp. 2029-2036
  5. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 22326668, please use {{cite journal}} with |pmid=22326668 instead.
  6. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15688064, please use {{cite journal}} with |pmid=15688064 instead.
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15130582, please use {{cite journal}} with |pmid=15130582 instead.
  8. ^ Jose M. González and Vicente Andrés (2011) "Synthesis, transport and incorporation into the nuclear envelope of A-type lamins and inner nuclear membrane proteins" Biochemical Society Transactions (2011) 39, (1758–1763)
  9. ^ M.C. King et al. (2006) "Karyopherin-mediated import of integral inner nuclear membrane proteins" Nature Vol 442|31 August 2006|doi:10.1038/nature05075
  10. ^ K. Chow, R.E. Factor, K.S. Ullmann (2012) ”The nuclear envelope environment and its cancer connections” Nature Reviews Cancer 12, 196-209 | doi: 10.1038/nrc3219
  11. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12118250, please use {{cite journal}} with |pmid=12118250 instead.
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