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Novel Insights Into Structure and Function of MRP8 (S100A8) and MRP14 (S100A9)

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Novel Insights Into Structure and Function of MRP8 (S100A8) and MRP14 (S100A9) View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1448 (1998) 200^211 Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9) Claus Kerkho¡ *, Martin Klempt, Clemens Sorg Institut fu«r Experimentelle Dermatologie, von-Esmarch-Str. 56, D-48149 Mu«nster, Germany Accepted 13 October 1998 Abstract The two migration inhibitory factor- (MIF)-related protein-8 (MRP8; S100A8) and MRP14 (S100A9) are two calcium- binding proteins of the S100 family. These proteins are expressed during myeloid differentiation, are abundant in granulocytes and monocytes, and form a heterodimeric complex in a Ca2-dependent manner. Phagocytes expressing MRP8 and MRP14 belong to the early infiltrating cells and dominate acute inflammatory lesions. In addition, elevated serum levels of MRP8 and MRP14 have been found in patients suffering from a number of inflammatory disorders including cystic fibrosis, rheumatoid arthritis, and chronic bronchitis, suggesting conceivable extracellular roles for these proteins. Although a number of possible functions for MRP8/14 have been proposed, the biological function still remains unclear. This review addresses recent developments regarding the MRP14-mediated promotion of leukocyte-endothelial cell-interactions and the characterization of MRP8/14 heterodimers as a fatty acid binding protein complex. In view of the current knowledge, the authors will hypothesize that MRP8 and MRP14 play an important role in leukocyte trafficking, but do not affect neutrophil effector functions. ß 1998 Elsevier Science B.V. All rights reserved. Keywords: Adhesion; Arachidonic acid; Calcium-binding protein; Cytoskeleton; Fatty acid-binding protein; In£ammation; Monocyte/macrophage; Polymorphonuclear leukocyte; Secretion 1. Introduction interact with target proteins such as protein kinases, protein phosphates, and ion-transporting proteins; Calcium has been implicated as a regulatory ion in and (3) these target proteins are part of the down- a variety of cellular processes such as muscle contrac- stream signaling elements which result in the com- tion, secretion, adhesion, synaptic transmission, cell- plex activation of transcription factors responsible cycle progression, and di¡erentiation. The calcium- for the cellular response to the stimulus. coupled responses consist of three major steps: (1) the The rise in intracellular calcium concentration is binding of ligands to cell surface receptors results transduced by the `activation' of calcium-binding in a rise of intracellular calcium concentration; proteins. There are four major classes of intracellular (2) calcium binds to intracellular calcium-binding calcium-binding proteins distinct from phospholipase proteins containing the EF-hand motif which then C and protein kinase C. These are (1) the calcium- modulated signaling proteins of the EF-hand family, (2) the calcium- and phospholipid-binding proteins * Corresponding author. Fax: +49-251-835-6549; of the annexin family, (3) a diverse group of cyto- E-mail: [email protected] skeletal calcium-binding and actin-modulating pro- 0167-4889 / 98 / $ ^ see front matter ß 1998 Elsevier Science B.V. All rights reserved. PII: S0167-4889(98)00144-X BBAMCR 14412 3-12-98 C. Kerkho¡ et al. / Biochimica et Biophysica Acta 1448 (1998) 200^211 201 teins, and (4) the high-capacity calcium storage pro- be localized in a cluster on human chromosome teins found in the microsomal compartment of the 1q21, and several murine homologues have been lo- ER. calized to a synthenic region on mouse chromosome This review addresses recent developments regard- 3. Therefore, it is suggested that the clustered organ- ing two low-molecular-mass calcium-binding pro- ization of these S100 genes has been conserved dur- teins containing EF-hand motifs, MRP8 and ing evolution. Heizmann's group proposed a new MRP14, which belong to the S100 protein family logical nomenclature for these genes, which is based (for reviews see [1^3]). We will brie£y review the old- on the physical arrangement on the chromosome er literature regarding the involvement of MRP8 and 1q21 [8]. According to this nomenclature, MRP8 is MRP14 in in£ammatory diseases and discuss in more referred to as S100A8, and MRP14 as S100A9, re- detail their protein and gene structure, their hetero- spectively. Heizmann and co-workers have recently dimer formation, their restricted cellular expression, identi¢ed two novel calcium-binding proteins belong- and their calcium-induced movement to cellular com- ing to the S100 protein family, S100A12 and partments as well as their release from cells. Finally, S100A13. The latter colocalizes with S100A1 on the we will summarize intra- and extracellular functions cluster, whereas S100A12 is localized between the of MRP8 and MRP14. In view of the current knowl- genes S100A8 and S100A9 [9,10]. edge some attention will be focused on the e¡ect It is worth mentioning that the ¢rst link between MRP8 and MRP14 have on lipid metabolism, and S100 family members and a speci¢c disease was made we will hypothesize that MRP8 and MRP14 have a for MRP8 and MRP14. It was speculated for con- regulatory role in neutrophil adhesion to endothe- siderable time that these two proteins could represent lium without further neutrophil activation. the proteins responsible for cystic ¢brosis, a specula- tion now superseded by the cloning of the gene en- coding the membrane protein cystic ¢brosis conduct- 2. MRP8 and MRP14 belong to the S100 protein ance regulator (CFTR). Nevertheless, it has been family shown that MRP8- and MRP14-expressing cells be- long to the early in¢ltrating cells and dominate acute Polymorphonuclear leukocytes (PMN) are the pre- in£ammatory lesions [11]. Phagocytes expressing dominant cell type present in areas of acute in£am- MRP8 and MRP14 are found in a variety of in£am- mation. They continuously circulate in the body, matory conditions, including rheumatoid arthritis, screening for the presence of altered cells, infecting allograft rejections, and in£ammatory bowel and microbes and foreign antigens. Two proteins abun- lung diseases [12,13]. In£ammatory disorders, such dant in monocytes and granulocytes were initially as chronic bronchitis, cystic ¢brosis, and rheumatoid puri¢ed using the monoclonal antibody 1C5, which arthritis, are associated with elevated plasma levels of was directed against the macrophage migration in- MRP8/14 [14,15]. Therefore, MRP8 and MRP14 are hibitory factor (MIF). Although the proteins them- widely used as marker proteins for activated or re- selves did not exhibit any migration inhibitory prop- cruited phagocytes. Although there are a number of erties they were called MIF-related proteins (MRP) hypotheses, the exact functions of both proteins (for a review see [4]). Computer-based homology remain unknown. Whether these proteins contribute search revealed that MRP8 is identical to the se- to leukocyte tra¤cking or may have a propagat- quence of the cystic ¢brosis (CF) antigen with one ing role in in£ammatory responses, remains to be exception. The sequence of MRP8 cDNA contains elucidated. an additional G residue in position 292 which shifts the reading frame of the last 15 amino acids. MRP8 is also referred by other names such as L1 light chain 3. MRP8 and MRP14 share structural homology with antigen, p8 and calgranulin A, and MRP14, corre- S100 proteins spondingly, as L1 heavy chain antigen, p14, and cal- granulin B [5^7]. Kyte and Doolittle hydropathy analysis indicates The genes encoding the S100 family were found to that MRP8 and MRP14 have hydropathic pro¢les BBAMCR 14412 3-12-98 202 C. Kerkho¡ et al. / Biochimica et Biophysica Acta 1448 (1998) 200^211 similar to other S100 proteins known to dimerize. Zn2 binding sites are apparently distinct and inde- Both MRP8 and MRP14 possess the same hydro- pendent of the two Ca2 binding domains [17]. phobic N- and C-terminal regions and hydrophilic The exon/intron structures of the MRP8 and EF-hands as calcyclin and S100L. These results imply MRP14 genes are similar to most other S100 genes that both MRP8 and MRP14 share structural ho- [18]. The MRP genes consist of three exons with mology with other S100 proteins. di¡erent lengths (33, 164, and 211 bp for MRP8 MRP8 and MRP14 are composed of two distinct and 28, 165, and 380 bp for MRP14) which are sep- helix^loop^helix motifs (EF-hand) £anked by hydro- arated by two introns of di¡erent lengths (484 and phobic regions at either terminus and separated by a 150 bp for MRP8, 292 bp and V2 kb for MRP14). central hinge region (Fig. 1). The C-terminal EF- In each gene, exon 1 encodes the untranslated region. hand has a higher a¤nity for Ca2 and encompasses The proteins are encoded by sequences in exon 2, 12 amino acids, whereas the N-terminal Ca2-bind- encoding the N-terminal 47 amino acids of MRP8 ing loop is formed by 14 amino acids. Alignment of and 50 amino acids of MRP14, respectively. The the calcium-binding loops of MRP8 and MRP14 exon 3 codes for the C-terminal 46 amino aids of with other members of the S100 protein family MRP8 and 64 amino acids of MRP14, respectively show that MRP14 contains the conserved sequence (Fig. 2). determinants necessary for calcium binding in sites I The sequence of human MRP8 cDNA has an open and II which are found in other S100 proteins. reading frame of 279 nucleotides predicting a protein MRP8 also has the standard binding loop in site II of 93 amino acids and a calculated Mr of 10 835, but a signi¢cant Glu33CAsp33 substitution at posi- whereas the human MRP14 contains an open read- tion 14 of the calcium-binding loop in the N-terminal ing frame of 352 nucleotides predicting a protein of pseudo EF-hand. Since this residue is known to play 114 amino acids and a calculated Mr of 13 242 [7].
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