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ABSTRACT: CONTENTS: Summary 695 I. Introduction 695 II. Structural analyses 696 III. Membrane-related functions 702 IV. Enzyme-related functions 703 V. Functional insights from proteome and transcriptome analyses 704 VI. Future perspectives 706 Acknowledgements 708 References 708 SUMMARY: Annexins are an homologous, structurally related superfamily of proteins known to associate with membrane lipid and cytoskeletal components. Their involvement in membrane organization, vesicle trafficking and signaling is fundamental to cellular processes such as growth, differentiation, secretion and repair. Annexins exist in some prokaryotes and all eukaryotic phyla within which plant annexins represent a monophyletic clade of homologs descended from green algae. Genomic, proteomic and transcriptomic approaches have provided data on the diversity, cellular localization and expression patterns of different plant annexins. The availability of 35 complete plant genomes has enabled systematic comparative analysis to determine phylogenetic relationships, characterize structures and observe functional specificity between and within individual subfamilies. Short amino termini and selective erosion of the canonical type 2 calcium coordinating sites in domains 2 and 3 are typical of plant annexins. The convergent evolution of alternate functional motifs such as 'KGD', redox-sensitive Cys and hydrophobic Trp/Phe residues argues for their functional relevance and contribution to mechanistic diversity in plant annexins. This review examines recent findings and advances in plant annexin research with special focus on their structural diversity, cellular and molecular interactions and their potential integrated functions in the broader context of physiological responses.
New Phytologist 09/2012; 196(3):695-712. · 6.64 Impact Factor
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Charles-Peter Xavier,
Raphael H Rastetter,
Margit Blömacher,
Maria Stumpf,
Mirko Himmel, Reginald O Morgan,
Maria-Pilar Fernandez,
Conan Wang,
Asiah Osman,
Yoshihiko Miyata,
Ruth A Gjerset,
Ludwig Eichinger,
Andreas Hofmann,
Stefan Linder,
Angelika A Noegel,
Christoph S Clemen
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ABSTRACT: CRN2 (synonyms: coronin 1C, coronin 3) functions in the re-organization of the actin network and is implicated in cellular processes like protrusion formation, secretion, migration and invasion. We demonstrate that CRN2 is a binding partner and substrate of protein kinase CK2, which phosphorylates CRN2 at S463 in its C-terminal coiled coil domain. Phosphomimetic S463D CRN2 loses the wild-type CRN2 ability to inhibit actin polymerization, to bundle F-actin, and to bind to the Arp2/3 complex. As a consequence, S463D mutant CRN2 changes the morphology of the F-actin network in the front of lamellipodia. Our data imply that CK2-dependent phosphorylation of CRN2 is involved in the modulation of the local morphology of complex actin structures and thereby inhibits cell migration.
Scientific Reports 01/2012; 2:241.
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Christoph S Clemen,
Karthikeyan Tangavelou,
Karl-Heinz Strucksberg,
Steffen Just,
Linda Gaertner,
Hanna Regus-Leidig,
Maria Stumpf,
Jens Reimann,
Roland Coras, Reginald O Morgan,
Maria-Pilar Fernandez,
Andreas Hofmann,
Stefan Müller,
Benedikt Schoser,
Franz-Georg Hanisch,
Wolfgang Rottbauer,
Ingmar Blümcke,
Stephan von Hörsten,
Ludwig Eichinger,
Rolf Schröder
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ABSTRACT: Mutations of the human valosin-containing protein gene cause autosomal-dominant inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. We identified strumpellin as a novel valosin-containing protein binding partner. Strumpellin mutations have been shown to cause hereditary spastic paraplegia. We demonstrate that strumpellin is a ubiquitously expressed protein present in cytosolic and endoplasmic reticulum cell fractions. Overexpression or ablation of wild-type strumpellin caused significantly reduced wound closure velocities in wound healing assays, whereas overexpression of the disease-causing strumpellin N471D mutant showed no functional effect. Strumpellin knockdown experiments in human neuroblastoma cells resulted in a dramatic reduction of axonal outgrowth. Knockdown studies in zebrafish revealed severe cardiac contractile dysfunction, tail curvature and impaired motility. The latter phenotype is due to a loss of central and peripheral motoneuron formation. These data imply a strumpellin loss-of-function pathogenesis in hereditary spastic paraplegia. In the human central nervous system strumpellin shows a presynaptic localization. We further identified strumpellin in pathological protein aggregates in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, various myofibrillar myopathies and in cortical neurons of a Huntington's disease mouse model. Beyond hereditary spastic paraplegia, our findings imply that mutant forms of strumpellin and valosin-containing protein may have a concerted pathogenic role in various protein aggregate diseases.
Brain 10/2010; 133(10):2920-41. · 9.46 Impact Factor
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Charles-Peter Xavier,
Raphael H Rastetter,
Maria Stumpf,
André Rosentreter,
Rolf Müller,
Jens Reimann,
Susanne Cornfine,
Stefan Linder,
Vanessa van Vliet,
Andreas Hofmann, Reginald O Morgan,
Maria-Pilar Fernandez,
Rolf Schröder,
Angelika A Noegel,
Christoph S Clemen
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ABSTRACT: Coronin 1C (synonyms: coronin-3, CRN2), a WD40 repeat-containing protein involved in cellular actin dynamics, is ubiquitously expressed in human tissues. Here, we report on the identification and functional characterization of two novel coronin 1C isoforms, referred to as CRN2i2 and CRN2i3, which also associate with F-actin. Analyses of the coronin 1C gene disclosed a single promoter containing binding sites for myogenic regulatory factors and an alternative first exon 1b present in intron 1, which give rise to the novel isoforms. Chromatin immunoprecipitation studies demonstrate MyoD binding to a region of the CRN2 gene, which contains a highly conserved E-box element in exon 1a. Gel-filtration assays suggest that the largest isoform 3 exists as a monomer, in contrast to isoform 1 and isoform 2 appearing as trimers. CRN2i3, which can be induced by MyoD, is exclusively expressed in well-differentiated myoblasts as well as in mature skeletal muscle tissue. In human skeletal muscle, CRN2i3 is a novel component of postsynaptic neuromuscular junctions and thin filaments of myofibrils. Together, our findings postulate a role for CRN2 isoforms in the structural and functional organization of F-actin in highly ordered protein complexes.
Journal of Molecular Biology 08/2009; 393(2):287-99. · 4.00 Impact Factor
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ABSTRACT: Annexin A2 is a highly expressed gene with important roles in cell membrane physiology and is frequently dysregulated in cancer. The objective of this study was to determine the pattern of expression and prognostic significance of annexin A2 protein in head and neck squamous cell carcinoma. We assessed both quantitative changes and qualitative distribution of annexin A2 mRNA and protein expression in normal and diseased tissues by immunohistochemistry, immunofluorescence and in situ hybridization. Annexin A2 expression was confined to the basal and suprabasal cells of normal epithelium and the protein cellular location was consistently observed at the cell membrane. Expression levels correlated with histopathological grade, showing significant suppression in moderately and poorly differentiated tumours. We conclude that annexin A2 exhibits a characteristic pattern of expression, distinct from other annexins and suggestive of a cell-specific functional role. The marked reduction of annexin A2 in poorly differentiated tumours and dysplastic tissue is expected to result in a loss of function aimed at the coordination of membrane signalling enzyme complexes, actin polymerization and extracellular matrix proteolysis. The phenotypic consequences may become manifest in an alteration of epithelial tissue growth and remodelling with secondary influence on tumour development, progression and metastasis.
Cancer Letters 06/2008; 263(1):89-98. · 4.24 Impact Factor
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ABSTRACT: This chapter discusses various aspects of coronin phylogeny, structure and function that are of specific interest. Two subfamilies of ancient coronins of unicellular pathogens such as Entamoeba, Trypanosoma, Leishmania and Acanthamoeba as well as of Plasmodium, Babesia, and Trichomonas are presented in the first two sections. Their coronins generally bind to F-actin and apparently are involved in proliferation, locomotion and phagocytosis. However, there are so far no studies addressing a putative role of coronin in the virulence of these pathogens. The following section delineates genetic anomalies like the chimeric coronin-fusion products with pelckstrin homology and gelsolin domains that are found in amoeba. Moreover, most nonvertebrate metazoa appear to encode CRN8, CRN9 and CRN7 representatives (for these coronin symbols see Chapter 2), but in e.g., Drosophila melanogaster and Caenorhabditis elegans a CRN9 is missing. The forth section deals with the evolutionary expansion of vertebrate coronins. Experimental data on the F-actin binding CRN2 of Xenopus (Xcoronin) including a Cdc42/Rac interactive binding (CRIB) motif that is also present in other members of the coronin protein family are discussed. Xenopus laevis represents a case for the expansion of the seven vertebrate coronins due to tetraploidization events. Other examples for a change in the number of coronin paralogs are zebrafish and birds, but (coronin) gene duplication events also occurred in unicellular protozoa. The fifth section of this chapter briefly summarizes three different cellular processes in which CRN4/CORO1A is involved, namely actin-binding, superoxide generation and Ca(2+)-signaling and refers to the largely unexplored mammalian coronins CRN5/CORO2A and CRN6/CORO2B, the latter binding to vinculin. The final section discusses how, by unveiling the aspects of coronin function in organisms reported so far, one can trace a remarkable evolution and diversity in their individual roles anticipating a rather complex and intricate involvement of coronins in a variety of cellular processes.
Sub-cellular biochemistry 02/2008; 48:98-109.
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ABSTRACT: The coronin gene family comprises seven vertebrate paralogs and at least five unclassified subfamilies in nonvertebrate metazoa, fungi and protozoa, but no representatives in plants or distant protists. All known members exhibit elevated structural conservation in two unique domains of unknown function (DUF1899 and DUF1900) interspaced by three canonical WD40 domains (plus additional pseudo domains) that form part of a 7-bladed beta-propeller scaffold, plus a C-terminal variable "coiled coil domain" responsible for oligomerization. Phylogenetic analysis of the N-terminal conserved region in known members (i.e.420 aa in 250 taxa) established the origin of the founding monomeric unit and a dimeric paralog in unicellular eukaryotes. The monomeric ancestor duplicated to two distinct lineages in basal metazoa and later propagated during the whole genome duplications in primitive chordates 450-550 million years ago to form six vertebrate-specific genes. The delineation of 12 subfamily clades in distinct phyla provided a rational basis for proposing a simplified, universal nomenclature for the coronin family in accordance with evolutionary history, structural relationships and functional divergence.Comparative genomic analysis of coronin subfamily locus maps and gene organization provided corroboratory evidence for their chromosomal dispersal and structural relatedness. Statistical analysis of evolutionary sequence conservation by profile hidden Markov models (pHMM) and the prediction of Specificity Determining Positions (SDPpred) helped to characterize coronin domains by highlighting structurally conserved sites relevant to coronin function and subfamily divergence. The incorporation of such evolutionary information into 3D models facilitated the distinction between candidate sites with a structural role versus those implicated in dynamic, actin-related cytoskeletal interactions. A highly conserved "KGD" motif identified in the coronin DUF1900 domain has been observed in other actin-binding proteins such as annexins and is a potential ligand for integrins and C2 domains known to be associated with structural and signalling roles in the membrane cytoskeleton. Molecular evolution studies provide a comprehensive overview of the structural history of the coronin gene family and a systematic methodology to gain deeper insight into the function(s) of individual members.
Sub-cellular biochemistry 02/2008; 48:41-55.
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ABSTRACT: Calcium-binding proteins regulate ion metabolism and vital signalling pathways in all living organisms. Our aim is to rationalize the molecular basis of their function by studying their evolution using computational biology techniques. Phylogenetic analysis is of primary importance for classifying cognate orthologs; profile hidden Markov models (HMM) of individual subfamilies discern functionally relevant sites by conservation probability analysis; and 3-dimensional structures display the integral protein in context. The major classifications of calcium-binding proteins, viz. EF-hand, C2 and ANX, exhibit structural diversity in their HMM fingerprints at the subfamily level, with functional consequences for protein conformation, exposure of receptor interaction sites and/or binding to membrane phospholipids. Calmodulin, S100 and annexin families were characterized in Petromyzon marinus (sea lamprey) to document genome duplication and gene creation events during the key evolutionary transition to primitive vertebrates. Novel annexins from diverse organisms revealed calcium-binding domains with accessory structural features that define their unique molecular fingerprints, protein interactivity and functional specificity. These include the first single-domain, bacterial annexin in Cytophaga hutchinsonii, the 21 tetrad annexins from the unicellular protist Giardia intestinalis, an ancestor to land plant annexins from the green alga Ostreococcus lucimarinus, invertebrate octad annexins and a critical polymorphism in human ANXA7. Receptor docking models supported the hypothesis of a potential interaction between annexin and C2 domains as a propitious mechanism for ensuring membrane translocation during signal transduction.
Biochimica et Biophysica Acta 12/2006; 1763(11):1238-49. · 4.66 Impact Factor
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ABSTRACT: Annexin A1 (ANXA1) protein expression was evaluated by Western blot in a series of 32 head and neck squamous cell carcinomas (HNSCCs) in a search for molecular alterations that could serve as useful diagnostic/prognostic markers. ANXA1 down-regulation was observed in 24 cases (75%) compared with patient-matched normal epithelium. In relation to clinicopathological variables, ANXA1 down-regulation was significantly associated with advanced T stages (P = 0.029), locoregional lymph node metastases (P = 0.038), advanced disease stage (P = 0.006), hypopharyngeal localization (P = 0.038), and poor histological differentiation (P = 0.005). ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions. All dysplastic tissues showed significantly reduced ANXA1 expression compared to a strong positive signal observed in adjacent normal epithelia (except basal and suprabasal cells). A close association was observed between ANXA1 expression and the histological grade in HNSCC. Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining. Our findings clearly identify ANXA1 as an effective differentiation marker for the histopathological grading of HNSCCs and for the detection of epithelial dysplasia.
American Journal Of Pathology 02/2004; 164(1):73-9. · 4.89 Impact Factor
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ABSTRACT: Annexin A11 is one of the 12 vertebrate subfamilies in the annexin superfamily of calcium/phospholipid-binding proteins, distinguishable by long, non-homologous N-termini rich in proline, glycine and tyrosine residues. As there is negligible structural information concerning this annexin subfamily apart from primary sequence data, we have cloned, expressed and purified recombinant mouse annexin A11 to investigate its structural and functional properties. CD spectroscopy reveals two main secondary-structure contributions, alpha-helix and random coil (approx. 30% each), corresponding mainly to the annexin C-terminal tetrad and the N-terminus respectively. On calcium binding, an increase in alpha-helix and a decrease in random coil are detected. Fluorescence spectroscopy reveals that its only tryptophan residue, located at the N-terminus, is completely exposed to the solvent; calcium binding promotes a change in tertiary structure, which does not affect this tryptophan residue but involves the movement of approximately four tyrosine residues to a more hydrophobic environment. These calcium-induced structural changes produce a significant thermal stabilization, with an increase of approx. 14 degrees C in the melting temperature. Annexin A11 binds to acidic phospholipids and to phosphatidylethanolamine in the presence of calcium; weaker calcium-independent binding to phosphatidylserine, phosphatidic acid and phosphatidylethanolamine was also observed. The calcium-dependent binding to phosphatidylserine is accompanied by an increase in alpha-helix and a decrease in random-coil contents, with translocation of the tryptophan residue towards a more hydrophobic environment. This protein induces vesicle aggregation but requires non-physiological calcium concentrations in vitro. A three-dimensional model, consistent with these data, was generated to conceptualize annexin A11 structure-function relationships.
Biochemical Journal 08/2003; 373(Pt 2):437-49. · 4.90 Impact Factor
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ABSTRACT: Annexin A13 (ANXA13) is believed to be the original founder gene of the 12-member vertebrate annexin A family, and it has acquired an intestine-specific expression associated with a highly differentiated intracellular transport function. Molecular characterization of this subfamily in a range of vertebrate species was undertaken to assess coding region conservation, gene organization, chromosomal linkage, and phylogenetic relationships relevant to its progenitor role in the structure-function evolution of the annexin gene superfamily. Protein diagnostic features peculiar to this subfamily include an alternate isoform containing a KGD motif, an elevated basic amino acid content with polyhistidine expansion in the 5'-translated region, and the conservation of 15% core tetrad residues specific to annexin A13 members. The 12 coding exons comprising the 58-kb human ANXA13 gene were deduced from BAC clone sequencing, whereas internal repetitive elements and neighboring genes in chromosome 8q24.12 were identified by contig analysis of the draft sequence from the human genome project. A unique exon splicing pattern in the annexin A13 gene was corroborated by coanalysis of mouse, rat, zebrafish, and pufferfish genomic DNA and determined to be the most distinct of all vertebrate annexins. The putative promoter region was identified by phylogenetic footprinting of potential binding sites for intestine-specific transcription factors. Mouse annexin A13 cDNA was used to map the gene to an orthologous linkage group in mouse chromosome 15 (between Sdc2 and Myc by backcross analysis), and the zebrafish cDNA permitted its localization to linkage group 24. Comparative analysis of annexin A13 from nine species traced this gene's speciation history and assessed coding region variation, whereas phylogenetic analysis showed it to be the deepest-branching vertebrate annexin, and computational analysis estimated the gene age and divergence rate. The unique, conserved aspects of annexin A13 primary structure, gene organization, and genetic maps identify it as the probable common ancestor of all vertebrate annexins, beginning with the sequential duplication to annexins A7 and A11 approximately 700 MYA, before the emergence of chordates.
Molecular Biology and Evolution 06/2002; 19(5):608-18. · 5.55 Impact Factor
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ABSTRACT: Alterations of annexin A1 (ANXA1) expression have been reported in various cancers. However, no data are available about the expression of this protein in nasopharyngeal carcinomas (NPCs). The objective of this study was to investigate the expression of ANXA1 in these tumors.
We examined noncancerous nasopharyngeal mucosa (4 cases) and NPC (20 cases) for ANXA1 expression using immunohistochemistry.
All tumor tissues showed markedly reduced ANXA1 expression compared with a strong positive signal observed in the corresponding normal epithelia. We found that ANXA1 expression is associated with the histological type in NPC. Only squamous cell carcinomas presented a positive ANXA1 signal in differentiated areas whereas all poorly differentiated tumors exhibited negative staining.
Our data show for the first time that ANXA1 expression is down-regulated in NPC and that its expression seems to be related with the squamous differentiation status of these tumors.
American Journal of Rhinology 19(5):483-7. · 1.36 Impact Factor
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ABSTRACT: We have identified and characterized a 12th subfamily of vertebrate annexins by systematic analysis of the primary structure, chromosomal mapping, and molecular evolution of unique cDNA and protein sequences from human and mouse. Distinctive features included rare expression, a codon deletion in conserved repeat 3, and an unusual ablation of the type II calcium-binding sites in tetrad core repeats 1, 3, and 4. The paralogy of novel annexin A10 (following revised nomenclature) was confirmed by FISH-mapping human ANXA10 to chromosome 4q33 and genetic linkage mapping mouse Anxa10 to midchromosome 8. Phylogenetic analysis established that the 5′ and 3′ halves of the annexin A6 octad are more closely related to annexins A5 and A10, respectively, than they are to each other. Molecular date estimates, paralogy linkage maps between human chromosomes 4 and 5, and annexin structural considerations led to the proposal that annexins A5 and A10 may have been the direct progenitors of annexin A6 octad formation via chromosomal duplication during the genome expansion in early chordates.
Genomics.
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ABSTRACT: The cDNA encoding novel human annexin 31 was utilized for chromosomal mapping, structural comparison, and phylogenetic analysis to clarify its genetic relationship to other annexins. The ANX31 gene locus was mapped by fluorescence in situ hybridization to human chromosome 1q21, remote from ten other paralogous human annexins on different chromosomes but near the epidermal differentiation gene complex, the S100A gene cluster and a breast-cancer translocation region. Protein homology testing and characterization of incompletely processed expressed sequence tags identified annexin 2 as the closest extant homologue. Maximum likelihood analysis confirmed its most recent common ancestor with vertebrate annexin 2 and validated its classification, in order of discovery, as annexin 31. This subfamily was formed approx. 500–600 million years ago, subsequent to the gene duplication that produced annexin 1. It has diverged rapidly and extensively, especially in the well-conserved and functionally critical type II calcium-binding sites.
Gene 227(1):33-38. · 2.34 Impact Factor
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ABSTRACT: Mouse annexin XI (anx11)2was cloned from a macrophage cDNA library and characterized by genetic linkage mapping, DNA sequencing, and structural comparison with other annexins. TheAnx11gene localized to mouse chromosome 14 in close linkage with theRarb, Plau,andWnt5agenes near the centromere and 1.8 cM distal from theAnx7gene. The open reading frame was flanked by long, untranslated regions and encoded a 503-amino-acid protein with 93.1% identity to its human orthologue. Its 189-aa amino terminus corresponded to the widely expressed variant 1 of two possible, alternatively spliced forms. A previously described peptide fromAplysia brasilianawas identified as a closely related invertebrate homologue. Since annexin XI is known to be localized in the nucleus at certain stages of development, the identification of a region in tetrad repeats 3 and 4 resembling the “chromo box” domain may be relevant to a nuclear regulatory function of annexin XI. Knowledge of the mouse cDNA sequence and genetic map location will assist in the analysis of genomic organization and expression and provide a useful animal model to investigate gene function and hereditary phenotype for annexin XI.
Genomics 37(3):366-374. · 3.02 Impact Factor
