The crystal structures of two spermadhesins reveal the CUB domain fold

Romero, Antonio; Romão, Maria João; Varela, Paloma F.; Kölln, Ingo; Dias, João M.; Carvalho, Ana Luı́sa; Sanz, Líbia; Töpfer‐Petersen, Edda; Calvete, Juan J.

doi:10.1038/nsb1097-783

Cited by 133 publications

(113 citation statements)

References 21 publications

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“…This led to the prediction that the CUB-binding site on IF might be formed by regions present in both the ␣-and ␤-domains. The crystal structures of several CUB domains are known (36)(37)(38)(39), and these show that their overall electrostatic potential surfaces are neutral, as is IF (this work). Comparison of the IF-Cbl complex with the CUB domain structures suggests that the nature of these interactions is primarily nonpolar or neutral hydrophilic and not electrostatic.…”

Section: Discussionmentioning

confidence: 86%

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

Mathews¹,

Gordon

Chen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The structure of intrinsic factor (IF) in complex with cobalamin (Cbl) was determined at 2.6-Å resolution. The overall fold of the molecule is that of an ␣6/␣6 barrel. It is a two-domain protein, and the Cbl is bound at the interface of the domains in a base-on conformation. Surprisingly, two full-length molecules, each comprising an ␣-and a ␤-domain and one Cbl, and two truncated molecules with only an ␣-domain are present in the same asymmetric unit. The environment around Cbl is dominated by uncharged residues, and the sixth coordinate position of Co 2؉ is empty. A detailed comparison between the IF-B12 complex and another Cbl transport protein complex, trans-Cbl-B12, has been made. The pH effect on the binding of Cbl analogues in transport proteins is analyzed. A possible basis for the lack of interchangeability of human and rat IF receptors is presented.5] is a water-soluble vitamin and is essential for the growth and development of all mammals, including humans. Cbl is a member of the corrinoid series of cobalt-containing compounds and is distinguished from some other members of this group by possessing a nucleotide side chain terminating in dimethylbenzimidazole (1, 2). It serves as a key enzymatic cofactor for a number of methyltransferase and mutase reactions occurring in nature (3). In mammals, it contributes the prosthetic group for two important enzymes, methionine synthase (a methyltransferase) and methylmalonylCoA mutase (1, 2, 4).In mammals, three proteins are involved in the uptake, transport, and storage of Cbl. These are gastric intrinsic factor (IF), trans-Cbl II (TC), and haptocorrin (HC). These are immunologically distinct proteins with a protein core of Ϸ46 kDa. IF and HC are heavily glycosylated, but TC is not (5, 6). In humans, the genes for IF and HC are located in chromosome 22 (7,8), whereas the gene for TC is located in chromosome 11 (9). Human IF contains 399-aa residues plus Ϸ15% carbohydrate, giving it a molecular mass of Ϸ60 kDa, as observed by gel filtration (10-13). All three proteins promote Cbl entry through endocytosis involving distinct cell surface receptors (5,(14)(15)(16)(17)(18)(19)(20).Dietary Cbl is bound first to HC in the gastric lumen but is transferred to IF in the duodenum after degradation of HC by pancreatic proteases. IF is responsible for transit of Cbl through the small intestine and delivery of it to the endothelial cells that line the ileum. The IF-Cbl complex is then recognized by the IF-Cbl receptor, cubilin (CUB), located on the luminal side of the intestinal mucosal cells, and mediates its internalization. Lysosomal degradation of the internalized IF-Cbl complex releases Cbl, which is then able to bind to TC, probably within the enterocyte. The TC-Cbl complex is then translocated across the basolateral membrane and released into the circulation, to be taken up by TC-Cbl receptor-mediated process by all cells in the body. Lysosomal dissociation of the complex then occurs along with transfer of Cbl to the coenzyme methyl-and Ado-Cbl in the cytoplasm and i...

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Section: Discussionmentioning

confidence: 86%

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

Mathews¹,

Gordon

Chen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…The CUB1 Module and Ca 2ϩ -binding Site II-The MAp19 CUB1 module is organized in two four-stranded ␤-sheets, each made of anti-parallel strands, providing further evidence that this topology, also observed in the corresponding module of human C1s and rat MASP-2, defines a particular CUB domain subset distinct from the plasma spermadhesins (31). As expected from sequence homologies, the MAp19 CUB1 module is structurally closer to its counterpart in rat MASP-2 (root mean square deviation ϭ 0.56 Å, based on 106 C␣ atoms) than to the C1s CUB1 module (root mean square deviation ϭ 0.94 Å, based on 99 C␣ atoms).…”

Section: Resultsmentioning

confidence: 99%

The X-ray Structure of Human Mannan-binding Lectin-associated Protein 19 (MAp19) and Its Interaction Site with Mannan-binding Lectin and L-ficolin

Gregory

Thielens

Matsushita

et al. 2004

Journal of Biological Chemistry

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MAp19 is an alternative splicing product of the MASP-2 gene comprising the N-terminal CUB1-epidermal growth factor (EGF) segment of MASP-2, plus four additional residues at its C-terminal end. Like fulllength MASP-2, it forms Ca 2؉ -dependent complexes with mannan-binding lectin (MBL) and L-ficolin. The x-ray structure of human MAp19 was solved to a resolution of 2.5 Å. It shows a head to tail homodimer held together by interactions between the CUB1 module of one monomer and the EGF module of its counterpart. A Ca 2؉ ion bound to each EGF module stabilizes the dimer interfaces. A second Ca 2؉ ion is bound to the distal end of each CUB1 module, through six ligands contributed by Glu 52 , Asp 60 , Asp 105 , Ser 107 , Asn 108 , and a water molecule. Compared with its counterpart in human C1s, the Nterminal end of the MAp19 CUB1 module contains a 7-residue extension that forms additional inter-monomer contacts. To identify the residues involved in the interaction of MAp19 with MBL and L-ficolin, point mutants were generated and their binding ability was determined using surface plasmon resonance spectroscopy. Six mutations at Tyr 59 , Asp 60 , Glu 83 , Asp 105 , Tyr 106 , and Glu 109 either strongly decreased or abolished interaction with both MBL and L-ficolin. These mutations map a common binding site for these proteins located at the distal end of each CUB1 module and stabilized by the Ca 2؉ ion.

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“…It is possible that the six Acp lipases may also play a role in lipid modification or in providing energy to the sperm, which may affect sperm motility and͞or viability. In vertebrates, sperm-egg interactions have been shown to be in part mediated by members of the lectin (63) and CRISP (42,43) protein classes. Although little is known about the carbohydrate moieties on the sperm surface of Drosophila, they seem important for sperm-egg interaction (64); thus, lectin-like Acps Acp29AB, CG1652, and CG1656 may perform an analogous function to lectin-like spermadhesins in mammals.…”

Section: Discussionmentioning

confidence: 99%

Comparative structural modeling and inference of conserved protein classes in Drosophila seminal fluid

Mueller

Ripoll

Aquadro

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

121

157

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The constituents of seminal fluid are a complex mixture of proteins and other molecules, most of whose functions have yet to be determined and many of which are rapidly evolving. As a step in elucidating the roles of these proteins and exposing potential functional similarities hidden by their rapid evolution, we performed comparative structural modeling on 28 of 52 predicted seminal proteins produced in the Drosophila melanogaster male accessory gland. Each model was characterized by defining residues likely to be important for structure and function. Comparisons of known protein structures with predicted accessory gland proteins (Acps) revealed similarities undetectable by primary sequence alignments. The structures predict that Acps fall into several categories: regulators of proteolysis, lipid modifiers, immunity͞ protection, sperm-binding proteins, and peptide hormones. The comparative structural modeling approach indicates that major functional classes of mammalian and Drosophila seminal fluid proteins are conserved, despite differences in reproductive strategies. This is particularly striking in the face of the rapid protein sequence evolution that characterizes many reproductive proteins, including Drosophila and mammalian seminal proteins.

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The crystal structures of two spermadhesins reveal the CUB domain fold

Cited by 133 publications

References 21 publications

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

The X-ray Structure of Human Mannan-binding Lectin-associated Protein 19 (MAp19) and Its Interaction Site with Mannan-binding Lectin and L-ficolin

Comparative structural modeling and inference of conserved protein classes in Drosophila seminal fluid

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