HMGA1
High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene.[1][2]
This gene encodes a non-histone chromatin protein involved in many cellular processes, including regulation of inducible gene transcription, DNA replication, heterochromatin organization, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells.
HMGA1 proteins are quite small (~10-12 kDa) and basic molecules, and consist of three AT-hooks with the RGRP (Arg-Gly-Arg-Pro) core motif, a novel cross-linking domain located between the second and third AT-hook, and a C-terminal acidic tail characteristic for the HMG family comprising HMGA, HMGB and HMGN proteins.
HMGA1-GFP fusion proteins are highly dynamic in vivo (determined using FRAP analysis), but in contrast also show nanomolar affinity to AT-rich DNA in vitro (determined biochemically), which might be explained due to the extensive post-transcriptional modifications in vivo. HMGA1 preferentially binds to the minor groove of AT-rich regions in double-stranded DNA using its AT-hooks. It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. HMGA1 proteins have high amounts of diverse posttranslational modifications and are located mainly in the nucleus, especially in heterochromatin, but also in mitochondria and the cytoplasm.
Recently it has been shown that HMGA1 proteins, HMGA1a and HMGA1b, can cross-link DNA fibers in vitro and can induce chromatin clustering in vivo suggesting a structural role of HMGA1 proteins in heterochromatin organization.[3]
At least seven transcript variants encoding two different isoforms (HMGA1a, HMGA1b) have been found for this gene.[4] The splice variant HMGA1c with only two AT hooks and no acidic tail is in discussion to be a real member of the HMGA family.
Mice lacking their variant of HMGA1, i.e., Hmga1-/- mice, are diabetic, show a cardiac hypertrophy and express low levels of the insulin receptor.[5]
Interactions
HMGA1 has been shown to interact with CEBPB[6] and Sp1 transcription factor.[6]
See also
References
- ↑ Friedmann M, Holth LT, Zoghbi HY, Reeves R (Nov 1993). "Organization, inducible-expression and chromosome localization of the human HMG-I(Y) nonhistone protein gene". Nucleic Acids Res 21 (18): 4259–67. doi:10.1093/nar/21.18.4259. PMC 310059. PMID 8414980.
- ↑ Reeves R, Beckerbauer L (Jun 2001). "HMGI/Y proteins: flexible regulators of transcription and chromatin structure". Biochim Biophys Acta 1519 (1-2): 13–29. doi:10.1016/S0167-4781(01)00215-9. PMID 11406267.
- ↑ Vogel, B; Löschberger, A; Sauer, M; Hock, R (Sep 1, 2011). "Cross-linking of DNA through HMGA1 suggests a DNA scaffold.". Nucleic Acids Research 39 (16): 7124–33. doi:10.1093/nar/gkr396. PMC 3167630. PMID 21596776.
- ↑ "Entrez Gene: HMGA1 high mobility group AT-hook 1".
- ↑ Robert K. Semple (2009). "From bending DNA to diabetes: the curious case of HMGA1". Journal of Biology 8 (7): 64. doi:10.1186/jbiol164. PMC 2736670. PMID 19664187.
- ↑ 6.0 6.1 Foti, Daniela; Iuliano Rodolfo; Chiefari Eusebio; Brunetti Antonio (Apr 2003). "A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription". Mol. Cell. Biol. (United States) 23 (8): 2720–32. doi:10.1128/MCB.23.8.2720-2732.2003. ISSN 0270-7306. PMC 152545. PMID 12665574.
Further reading
- Hui H, Perfetti R (2002). "Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood.". Eur. J. Endocrinol. 146 (2): 129–41. doi:10.1530/eje.0.1460129. PMID 11834421.
- Van Maele B, Debyser Z (2005). "HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins.". AIDS reviews 7 (1): 26–43. PMID 15875659.
- Van Maele B, Busschots K, Vandekerckhove L et al. (2006). "Cellular co-factors of HIV-1 integration.". Trends Biochem. Sci. 31 (2): 98–105. doi:10.1016/j.tibs.2005.12.002. PMID 16403635.
- Reeves R, Nissen MS (1990). "The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure.". J. Biol. Chem. 265 (15): 8573–82. PMID 1692833.
- Nissen MS, Langan TA, Reeves R (1991). "Phosphorylation by cdc2 kinase modulates DNA binding activity of high mobility group I nonhistone chromatin protein.". J. Biol. Chem. 266 (30): 19945–52. PMID 1939057.
- Eckner R, Birnstiel ML (1989). "Cloning of cDNAs coding for human HMG I and HMG Y proteins: both are capable of binding to the octamer sequence motif.". Nucleic Acids Res. 17 (15): 5947–59. doi:10.1093/nar/17.15.5947. PMC 318252. PMID 2505228.
- Johnson KR, Lehn DA, Reeves R (1989). "Alternative processing of mRNAs encoding mammalian chromosomal high-mobility-group proteins HMG-I and HMG-Y.". Mol. Cell. Biol. 9 (5): 2114–23. PMC 363005. PMID 2701943.
- Palvimo J, Linnala-Kankkunen A (1989). "Identification of sites on chromosomal protein HMG-I phosphorylated by casein kinase II.". FEBS Lett. 257 (1): 101–4. doi:10.1016/0014-5793(89)81796-X. PMID 2806554.
- Karlson JR, Mørk E, Holtlund J et al. (1989). "The amino acid sequence of the chromosomal protein HMG-Y, its relation to HMG-I and possible domains for the preferential binding of the proteins to stretches of A-T base pairs.". Biochem. Biophys. Res. Commun. 158 (3): 646–51. doi:10.1016/0006-291X(89)92770-8. PMID 2920035.
- Lund T, Dahl KH, Mørk E et al. (1987). "The human chromosomal protein HMG I contains two identical palindrome amino acid sequences.". Biochem. Biophys. Res. Commun. 146 (2): 725–30. doi:10.1016/0006-291X(87)90589-4. PMID 3619901.
- Leger H, Sock E, Renner K et al. (1995). "Functional interaction between the POU domain protein Tst-1/Oct-6 and the high-mobility-group protein HMG-I/Y.". Mol. Cell. Biol. 15 (7): 3738–47. PMC 230612. PMID 7791781.
- John S, Reeves RB, Lin JX et al. (1995). "Regulation of cell-type-specific interleukin-2 receptor alpha-chain gene expression: potential role of physical interactions between Elf-1, HMG-I(Y), and NF-kappa B family proteins.". Mol. Cell. Biol. 15 (3): 1786–96. PMC 230403. PMID 7862168.
- Farnet CM, Bushman FD (1997). "HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro.". Cell 88 (4): 483–92. doi:10.1016/S0092-8674(00)81888-7. PMID 9038339.
- Miller MD, Farnet CM, Bushman FD (1997). "Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition.". J. Virol. 71 (7): 5382–90. PMC 191777. PMID 9188609.
- Huth JR, Bewley CA, Nissen MS et al. (1997). "The solution structure of an HMG-I(Y)-DNA complex defines a new architectural minor groove binding motif.". Nat. Struct. Biol. 4 (8): 657–65. doi:10.1038/nsb0897-657. PMID 9253416.
- Currie RA (1998). "Functional interaction between the DNA binding subunit trimerization domain of NF-Y and the high mobility group protein HMG-I(Y).". J. Biol. Chem. 272 (49): 30880–8. doi:10.1074/jbc.272.49.30880. PMID 9388234.
- Chin MT, Pellacani A, Wang H et al. (1998). "Enhancement of serum-response factor-dependent transcription and DNA binding by the architectural transcription factor HMG-I(Y).". J. Biol. Chem. 273 (16): 9755–60. doi:10.1074/jbc.273.16.9755. PMID 9545312.
- Chiappetta G, Tallini G, De Biasio MC et al. (1998). "Detection of high mobility group I HMGI(Y) protein in the diagnosis of thyroid tumors: HMGI(Y) expression represents a potential diagnostic indicator of carcinoma.". Cancer Res. 58 (18): 4193–8. PMID 9751634.
- Vogel, B; Löschberger, A; Sauer, M; Hock, R (Sep 1, 2011). "Cross-linking of DNA through HMGA1 suggests a DNA scaffold.". Nucleic Acids Research 39 (16): 7124–33. doi:10.1093/nar/gkr396. PMC 3167630. PMID 21596776.
External links
- HMGA1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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