Novel Functional Features of the LIS-H Domain: Role in Protein Dimerization, Half-Life and Cellular Localization

Gerlitz, Gabi; Darhin, Enbal; Giorgio, Giovanna; Bazzoli, Franco; Reiner, Orly

doi:10.4161/cc.4.11.2151

Cited by 76 publications

(68 citation statements)

References 47 publications

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“…LisH domains are found in a variety of proteins, the most famous being lissencephaly-1, a gene mutated in the human neuronal migration disorder lissencephaly (33). Interestingly, LisH domain in lissencephaly-1 is involved in the dimerization of the protein, and LisH domains in other proteins have been shown to promote homo-and hetero-dimerization and oligomerization of proteins (34,35). Thus, it is likely that RanBP9 exists as dimers or oligomers, lending to the notion that RanBP9 may be able to scaffold multiple APP, LRP, and BACE1 molecules simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Lakshmana

Yoon

Chen

et al. 2009

Journal of Biological Chemistry

144

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Accumulation of the amyloid ␤ (A␤) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer disease. We previously demonstrated that the C-terminal 37 amino acids of lipoprotein receptor-related protein (LRP) robustly promoted A␤ generation independent of FE65 and specifically interacted with Ran-binding protein 9 (RanBP9). In this study we found that RanBP9 strongly increased BACE1 cleavage of APP and A␤ generation. This pro-amyloidogenic activity of RanBP9 did not depend on the KPI domain or the Swedish APP mutation. In cells expressing wild type APP, RanBP9 reduced cell surface APP and accelerated APP internalization, consistent with enhanced ␤-secretase processing in the endocytic pathway. The N-terminal half of RanBP9 containing SPRY-LisH domains not only interacted with LRP but also with APP and BACE1. Overexpression of RanBP9 resulted in the enhancement of APP interactions with LRP and BACE1 and increased lipid raft association of APP. Importantly, knockdown of endogenous RanBP9 significantly reduced A␤ generation in Chinese hamster ovary cells and in primary neurons, demonstrating its physiological role in BACE1 cleavage of APP. These findings not only implicate RanBP9 as a novel and potent regulator of APP processing but also as a potential therapeutic target for Alzheimer disease. The major defining pathological hallmark of Alzheimer disease (AD)2 is the accumulation of amyloid ␤ protein (A␤), a neurotoxic peptide derived from ␤-and ␥-secretase cleavages of the amyloid precursor protein (APP). The vast majority of APP is constitutively cleaved in the middle of the A␤ sequence by ␣-secretase (ADAM10/TACE/ADAM17) in the non-amyloidogenic pathway, thereby abrogating the generation of an intact A␤ peptide. Alternatively, a small proportion of APP is cleaved in the amyloidogenic pathway, leading to the secretion of A␤ peptides (37-42 amino acids) via two proteolytic enzymes, ␤-and ␥-secretase, known as BACE1 and presenilin, respectively (1).The proteolytic processing of APP to generate A␤ requires the trafficking of APP such that APP and BACE1 are brought together in close proximity for ␤-secretase cleavage to occur. We and others have shown that the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytosis receptor (2), binds to APP and alters its trafficking to promote A␤ generation. The loss of LRP substantially reduces A␤ release, a phenotype that is reversed when full-length (LRP-FL) or truncated LRP is transfected in LRP-deficient cells (3, 4). Specifically, LRP-CT lacking the extracellular ligand binding regions but containing the transmembrane domain and the cytoplasmic tail is capable of rescuing amyloidogenic processing of APP and A␤ release in LRP deficient cells (3). Moreover, the LRP soluble tail (LRP-ST) lacking the transmembrane domain and only containing the cytoplasmic tail of LRP is sufficient to enhance A␤ secretion (5). This activity of LRP-ST is achieved by promoting APP/BACE1 intera...

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Section: Discussionmentioning

confidence: 99%

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Lakshmana

Yoon

Chen

et al. 2009

Journal of Biological Chemistry

144

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“…Mutations in this region of the protein abolish the repression activity of the protein as well as its interaction with chromatin and other components of the repression machinery 36 . Furthermore it has been suggested that this region of the protein is also required for the nuclear localization of TBL1 and it is proposed that, in general, LisH mutations are likely to be associated with disease 47 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery

Oberoi

Fairall

Watson

et al. 2011

Nat Struct Mol Biol

138

156

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Eukaryotic transcriptional repressors function by recruiting large co-regulatory complexes that target histone deacetylase enzymes to gene promoters/enhancers. Transcriptional repression complexes, assembled by the co-repressor NCoR, and its homologue SMRT, play critical roles in many processes including development and metabolic physiology. The core repression complex involves the recruitment of three proteins: HDAC3, GPS2 and TBL1 to a highly conserved repression domain within SMRT and NCoR. We have used a variety of structural and functional approaches to gain insight into the assembly, stoichiometry and biological role of this complex. We report the crystal structure of the tetrameric oligomerization domain of TBL1, which interacts with both SMRT and GPS2, and the NMR structure of the interface complex between GPS2 and SMRT. These structures, together with computational docking, mutagenesis and functional assays, reveal the assembly mechanism and stoichiometry of the co-repressor complex.The regulated repression of transcription plays a key role in many biological processes. These include cell fate decisions during development and cellular differentiation, as well as the maintenance of homeostasis. SMRT and NCoR are large homologous co-repressor proteins that were identified through their role in transcriptional repression by many 5 Corresponding author: john.schwabe@le.ac.uk. 4 These authors should be considered co-first authors. Author ContributionsThe contributions of J.O., L.F. & P.W. were critical to the final manuscript and these authors should be considered co-first authors. J.O. (assisted by J.Gooch) performed most of the protein cloning, expression, purification and interaction mapping, although important preliminary experiments were performed by B.K. J.O. prepared the GPS2-SMRT complex for NMR structure determination which was carried out by J-C.Y. and D.N. Crystallizations were performed primarily by J.O., with some later trials by J.Greenwood and L.F. Crystal structure determinations were performed by L.F., J.O. and J.W.R.S. The interaction motifs in GPS2 and SMRT were identified by J.W.R.S. and tested by pull-down experiments by J.O. Fluorescence polarization, co-immunoprecipitation and co-transfection/ purification assays were performed by P.W. The two-hybrid assays, gel filtrations and NMR comparisons of WT and MT TBL1 were performed by P.W., Z.C. and B.G. In silico docking experiments were performed by T.K. The laboratories of L.N. and D.N. provided experimental expertise for transfection and NMR studies respectively. J.W.R.S. planned and supervised the project and prepared the manuscript with assistance from the other authors. Accession Codes1H, 13C and 15N NMR resonance assignments for the SMRT(167-207) -GPS2(53-90) complex have been deposited at the BioMagResBank under accession code 17271, and the coordinates have been deposited under the pdb accession code 215G. The TBL1 X-ray structures have been deposited with the PDB codes (2XTC, 2XTD & 2XTE). When purified from HeLa cell extr...

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“…domains are involved in homodimer formation of various proteins (Gerlitz et al, 2005;Kim et al, 2004b;Mikolajka et al, 2006). The FOP and FOR20 proteins are also distantly related to the N terminus of the centrosomal OFD1 (oral facial digital 1) protein (Fig.…”

Section: Identification Of a Fop-related Protein In Ciliated Speciesmentioning

confidence: 99%

Control of ciliogenesis by FOR20, a novel centrosome and pericentriolar satellite protein

Sedjaï

Acquaviva

Chevrier

et al. 2010

Journal of Cell Science

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SummaryCilia and flagella are evolutionary conserved organelles that generate fluid movement and locomotion, and play roles in chemosensation, mechanosensation and intracellular signalling. In complex organisms, cilia are highly diversified, which allows them to perform various functions; however, they retain a 9+0 or 9+2 microtubules structure connected to a basal body. Here, we describe FOR20 (FOPrelated protein of 20 kDa), a previously uncharacterized and highly conserved protein that is required for normal formation of a primary cilium. FOR20 is found in PCM1-enriched pericentriolar satellites and centrosomes. FOR20 contains a Lis1-homology domain that promotes self-interaction and is required for its satellite localization. Inhibition of FOR20 expression in RPE1 cells decreases the percentage of ciliated cells and the length of the cilium on ciliated cells. It also modifies satellite distribution, as judged by PCM1 staining, and displaces PCM1 from a detergent-insoluble to a detergent-soluble fraction. The subcellular distribution of satellites is dependent on both microtubule integrity and molecular motor activities. Our results suggest that FOR20 could be involved in regulating the interaction of PCM1 satellites with microtubules and motors. The role of FOR20 in primary cilium formation could therefore be linked to its function in regulating pericentriolar satellites. A role for FOR20 at the basal body itself is also discussed.

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Novel Functional Features of the LIS-H Domain: Role in Protein Dimerization, Half-Life and Cellular Localization

Cited by 76 publications

References 47 publications

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery

Control of ciliogenesis by FOR20, a novel centrosome and pericentriolar satellite protein

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