bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cocatalytic Zinc Sites
Authors: Auld David S 
Published: April 2006

AbstractCocatalytic zinc sites occur in enzymes where two or three metals are closely grouped to bring about catalysis. There are over four dozen representatives of this type of zinc site with the great majority belonging to the Class III hydrolases. A novel feature of these sites is the bridging of two of the metal sites by a side chain moiety of a single amino acid residue, such as the ring nitrogens of the imidazole group of histidine or the carboxylate oxygens of aspartic acid, glutamic acid, or of a carboxylated lysine, LysCO2−. Such an interaction requires the metals to be in close proximity to each other. The ligands to cocatalytic zinc sites often come from nearly the entire length of the protein, indicating that the metal sites may be important to the overall fold of the protein as well as to catalytic function. The secondary structure of the protein plays a major role in providing the ligands to these sites. In most cases, ligands are provided by amino acids residing within one or two residues before or after a β‐sheet or an α‐helix. The zinc ions are often penta‐coordinate and arranged in a trigonal bipyramidal geometry. The bridging amino acids and H2O probably have critical roles in catalysis. Their dissociation from either metal atom during catalysis will change the charge on the metal promoting its action as a Lewis acid or allowing interaction with an electronegative atom of the substrate. Thus, it can be envisioned for hydrolytic enzymes that substrate binding involves one zinc site acting as a template for substrate binding, while the other zinc site provides hydroxide for nucleophilic attack on the sp2center of the ester or amide bond of the substrate. In the next step, the roles of the metals can be reversed. In this manner, the metal atoms and their associated ligands play specific roles in each step of the reaction that works to bring about catalysis. The ligands in these sites, in particular the histidines, are often involved in further hydrogen‐bonding interactions with other amino acids. These interactions should effect the charge on the metal and the stability of the metal complex, thus fine‐tuning catalysis and the stability of the metal sites.
Protein Interface Zinc Sites: The Role of Zinc in the Supramolecular Assembly of Proteins and in Transient Protein–Protein Interactions
Authors: Maret Wolfgang 
Published: April 2006

AbstractNew roles are emerging for zinc in protein quaternary structure and supramolecular assemblies. When zinc bridges the interfaces of proteins via ligands provided by different polypeptide chains, it is either essential for the interaction or it serves mainly as a stabilizing factor. Zinc can cross‐link four, three, or more commonly, two protein monomers. Functions of protein interface zinc sites include catalysis, inhibition of enzymatic or other activity, packaging of proteins for storage, dimerization of proteins, formation of protein/receptor complexes, and construction of molecular scaffolds. Tight control of the availability of zinc and ligand‐centered redox reactions in zinc/thiolate coordination environments of protein interface zinc sites suggest mechanisms for modulating transient protein–protein interactions.
Zinc Modules in Nuclear Hormone Receptors
Authors: Devarakonda Srikripa , Rastinejad Fraydoon 
Published: April 2006

AbstractNuclear hormone receptors are a family of transcription factors that modulate the transcription of target genes in response to their respective hormones. By activating expression of gene networks, they coordinate complex events involving development, differentiation, and response to diverse stimuli. Most receptors function as homo‐ or heterodimers and activate the target genes by binding selectively to regulatory sequences called DNA response elements (DRE) in the promoter region of the gene. The majority of members in this family recognize slight variations of the same consensus hexameric sequence – AGGTCA, through their DNA binding domains (DBD). The DREs contain the core hexameric sequence in various extended and bipartite configurations. The DBD consists of two zinc binding modules that fold onto each other to form a scaffold that is responsible for DNA binding and recognition. A series of three‐dimensional structures obtained from NMR and X‐ray crystallography have allowed the visualization of the DBDs alone and in their functional assemblies on the corresponding DREs. This chapter describes in detail the molecular and structural characteristics of the DBDs including their C‐terminal extensions as well as the topology of the various DREs that these receptors bind to. These features illustrate how a superfamily of receptors with highly conserved DNA binding domains can distinguish between closely related response elements. The structures described also indicate how cooperation between receptors enhances their joint affinity and selectivity for correctly configured sites.
Insulin
Authors: David Smith G 
Published: April 2006

Abstract

The protein hormone insulin, produced in the pancreas and stored in granules, interacts, after secretion into the blood stream, with the extracellular domain of the insulin receptor. This interaction initializes a signal transduction cascade that ultimately results in glucose absorption and metabolism. In the presence of zinc ion, insulin crystallizes as a threefold symmetric T
6
hexamer complexed to two zinc ions. When phenol,
m
‐cresol, or resorcinol is present in the crystallizing media, the first eight residues of all B‐chains undergo a conformational change from extended to α‐helical producing an R
6
hexamer. In the presence of thiocyanate or chloride ion, only residues 4 through 8 in the B‐chains of one trimer undergo the conformational change to produce a T
3
R
3
f
hexamer. This allosteric behavior of the insulin hexamer has been observed in the solid state as well as in solution. Like the T
6
hexamer, each zinc ion that lies on the crystallographic threefold axis is octahedrally coordinated by NE2s of three symmetry related HisB10 residues and three water molecules. Because of the conformational transition from T to either R or R
f
, there is not sufficient space in an R‐ or R
f
‐state trimer to accommodate octahedral coordination, and, therefore, zinc adopts tetrahedral coordination through bonds to the three symmetry related HisB10 NE2 atoms and either to a water molecule or to a chloride ion. In the case of T
3
R
3
f
hexamers, three additional zinc binding sites exist between symmetry related R
f
‐state monomers in which each zinc ion is coordinated by NE2 of a second orientation of the side chain of HisB10, NE2 of HisB5 of an adjacent monomer, and two chloride ions. From a total of 34 crystal structures of hexameric insulin, mean ZnNE2 bond distances of 2.00 or 2.10 Å are observed in tetrahedral or octahedral geometry, respectively.
RINGDomain Proteins
Authors: Dominguez Cyril , Folkers Gert E , Boelens Rolf 
Published: April 2006

AbstractThe RING domain is a cysteine‐rich sequence motif that can bind two zinc atoms. In the canonical RING motif, also called the C3HC4 motif, one zinc ion is bound to four cysteines, and the other ion to three cysteines and a histidine. The tetrahedral coordination is atypical and referred to as a ‘cross‐brace’ motif. There are now more than 380 RING motifs identified in the human genome. The RING domain has been shown to mediate a crucial step in the ubiquitination pathway that targets protein substrates for degradation by the 26 S proteasome. This pathway involves three enzymes, and the RING finger proteins have been classified in this scheme as ubiquitin ligases. There are actually nine structures of RING domains solved by X‐ray and NMR. The βαβ fold of the RING domain is conserved among all structures. The structures of RING domains in complex with other proteins involved in the ubiquitination pathway provide considerable insight into the molecular basis of ubiquitination. Recently, ubiquitination has been shown to be not only a simple protein removal system but also an indispensable regulatory process. This is underscored by the observation that many diseases, such as cancer and Parkinson's disease, are due to mutations in RING domains that prevent an efficient ubiquitination and degradation process. In this review, we compare the different structures of RING domains, analyze their functional aspects through structural information of RING domains in complex with other proteins, and describe medical aspects of RING finger proteins involved in cancer and Parkinson's disease.
LIM domain proteins
Authors: Kontaxis Georg , Bister Klaus , Konrat Robert 
Published: April 2006

AbstractLIM domain proteins are implicated in fundamental developmental processes, and the functional hallmark of all LIM domains is presumably the mediation of protein–protein interactions. Although originally identified in LIM‐homeodomain proteins, LIM domains have now been identified in a variety of proteins that lack homeodomains, either being entirely composed of LIM domains or containing additional functional domains of various types (e.g. kinase domains). The LIM domain contains a distinct cysteine‐rich motif that was first identified in the protein products of three genes –lin‐1,isl1, andmec‐3. The LIM motif is composed of two zinc finger structures separated by a two‐amino acid spacer and comprises the conserved sequence CX2CX16 − 23HX2CX2CX2CX16 − 21CX2(C/H/D).
FYVE
Domain
Authors: Kutateladze Tatiana G , Overduin Michael 
Published: April 2006

Abstract
The FYVE domain is a 65‐residue module that contains two tetrahedral zinc coordination centers. The zinc ions are bound by eight cysteine residues in a cross‐braced topology, providing structural stability. The FYVE domain is usually present as a single module or, more rarely, as a tandem repeat in eukaryotic proteins involved in a variety of biological processes including membrane trafficking and phosphoinositide metabolism. The biochemical function of the FYVE domain is the specific recognition of phosphatidylinositol 3‐phosphate [PtdIns(3)P], a phospholipid that is most concentrated in endocytic membranes. Structures, zinc coordination, and PtdIns(3)P binding modes of three FYVE domains have recently been characterized, providing mechanistic insights into their contributions to endocytosis, signal transduction, and cytoskeletal organization.
Methionine Aminopeptidase
Authors: Matthews Brian W 
Published: April 2006

AbstractThe methionine aminopeptidases represent a novel class of metalloprotease generally having two cobalt ions in the active site. The proteins consist of two topologically similar domains folded with a ‘pita‐bread’ motif. Structural analysis of various inhibitor complexes with theEscherichia colienzyme and other members of the family have suggested a putative mechanism of catalysis related to that originally proposed for thermolysin.
Neprilysin
Authors: Dale Glenn E , Oefner Christian 
Published: April 2006

AbstractNeprilysin (NEP), a thermolysin‐like zinc metalloendopeptidase, is the major enzyme involved in the metabolic inactivation of a number of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin, and the atrial natriuretic factor. NEP is an integral plasma membrane endopeptidase of the M13 family of zinc peptidases. Other related mammalian NEP‐like enzymes include the endothelin‐converting enzymes (ECE‐1 and ECE‐2), KELL and PEX. A number of novel mammalian homologues of NEP have also recently been described. Owing to the physiological importance of NEP in the modulation of nociceptive and pressor responses, there is considerable interest in inhibitors of this enzyme as novel analgesics and antihypertensive agents. Here we provide an overview of this pharmacologically important protein protease family.
Astacin
Authors: Stöcker Walter , Yiallouros Irene 
Published: April 2006

AbstractThe mono‐zinc endopeptidase astacin (EC 3.4.24.21) is a prototype for the astacin family and for the metzincin superfamily of metalloproteinases. Some astacins are digestive enzymes of invertebrates, but the majority serve functions during embryonic development, pattern formation, and epithelial differentiation throughout the animal kingdom. The catalytic protease domain of the astacins is topologically similar to the corresponding domains of the matrix metalloproteinases (MMPs), the adamalysins/reprolysins/ADAMs (a disintegrin and metalloprotease), the bacterial serralysins, and several other groups of zinc peptidases. They have in common a conserved zinc binding sequence, HEXXHXXGXXH, containing three histidines and a catalytically important glutamic acid residue, which acts as a general base during catalysis. Furthermore, there is a strictly conserved methionine‐containing turn structure beneath the active site, the Met‐turn, which gave rise to the designationmetzincinsfor this superfamily of metalloproteins. In astacin, in addition to the three histidine residues of the zinc binding motif, the metal is ligated by the Glu93‐bound ‘activated’ water and by Tyr149, positioned in the Met‐turn, resulting in a trigonal bipyramidal coordination sphere. This overview treats the structural basis for the function of astacin‐like proteases, including proenzyme activation, cleavage specificity, substrate and inhibitor kinetics, catalysis, and metal binding. It also pinpoints shared commonalities and subtle differences between astacin and other metzincins.
Matrix Metalloproteinases
Authors: Bode Wolfram , Maskos Klaus 
Published: April 2006

AbstractThe matrix metalloproteinases (MMPs) constitute a family of (in man) 23 different extracellular soluble/cell surface–anchored multidomain zinc endopeptidases, all of which exhibit a common catalytic domain of a metzincin‐like topology, that is, possess a Met‐containing tight turn and carry an extended His‐Glu‐Xaa‐Xaa‐His‐Xaa‐Xaa‐Gly‐Xaa‐Xaa‐His zinc‐binding consensus segment enwrapping the catalytic zinc, with the three histidine imidazole side chains and a nucleophilic water ligating the catalytic zinc, and the glutamine side chain presumably acting as a proton shuttle. The MMPs are involved not only in extracellular matrix degradation but also in a number of other biological processes such as shedding of membrane‐bound growth factor and cytokine precursors, pro‐proteinase activation, or inhibitor inactivation. Normally, their proteolytic activity is precisely regulated by endogenous protein inhibitors, in particular, by the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in serious diseases such as arthritis, tumor growth, and metastasis, thus rendering the MMPs attractive targets for inhibition therapy. Individual vertebrate MMPs have been named according to their presumed substrates or classified by sequential (chronological) numbers, which run from MMPs 1 to 28. These MMPs are synthesized with an N‐terminal signal sequence, a pro‐domain, and a catalytic domain containing the catalytic zinc, a structural zinc, and up to three calcium ions. Additionally, most MMPs possess a C‐terminal ion containing hemopexin‐like domain, which, in the membrane‐bound MMPs, is followed by a transmembrane helix and a cytoplasmic domain, or a glycosil phosphatidyl inositol (GPI) anchor. This overview presents common and special structural features of the MMPs, in particular of their catalytic domain.
Serralysin
Authors: Baumann Ulrich 
Published: April 2006

AbstractSerralysins (EC 3.4.24.40) are a family of 50‐kDa metalloproteases from gram‐negative enterobacteria. They are members of the metzincin clan of endopeptidases and possess the conserved zinc binding HEXXHXXGXXHP sequence motif, followed by a conserved methionine. The three‐dimensional structure shows that serralysins possess two domains; besides the typical metzincin‐protease domain that resides within the N‐terminal 220 amino acids, there is an extended C‐terminal β‐sheet domain. This domain contains six glycine‐rich tandem repeats GGXGXDXLX characteristic for the RTX‐toxin family. These repeats bind calcium ions.Recent studies include directed mutagenesis in order to clarify the function of the conserved methionine as well as the crystal‐structure determination of complexes between serralysins and their cognate inhibitors. The latter shows inhibition by a coordinative bond between the inhibitor's N‐terminus and the catalytic zinc ion.
Metallocarboxypeptidases
Authors: Vendrell Josep , Aviles Francesc X , Fricker Lloyd D 
Published: April 2006

AbstractMetallocarboxypeptidases (CP) catalyze the removal of C‐terminal amino acids from proteins and/or peptides. The different members of the CP family differ in their specificity for C‐terminal residues and physiological function and can be divided into two subfamilies. Members of the A/B subfamily are generally produced as proenzymes, contain an approximately 300‐residue CP catalytic domain, have greatest amino acid sequence identity to the exocrine pancreatic enzymes CPA and CPB, and prefer hydrophobic or basic residues. They function in the breakdown of peptides in food or in other physiological processes ranging from inflammation to fibrinolysis. Members of the N/E group cleave C‐terminal basic residues and are not produced as inactive proenzymes but contain an approximately 80‐residue region following the 300‐residue CP domain with structural homology to transthyretin. They act either extra‐ or intracellularly in the processing of peptide hormones and neurotransmitters and other physiologically relevant peptides.The tertiary folding of CPs corresponds to the α/β hydrolase fold and is formed by a central mixed parallel/antiparallel eight‐strand β‐sheet, with a 120° twist between the first and the last strand, over which eight α‐helices pack on both sides to form a globular molecule. All of the enzymatically active CPs bind one atom of Zn2+at the active site. Some members of the CP family that are inactive against standard CP substrates lack some of the cation‐binding ligands and may therefore not be able to bind the metal.
Pitrilysins/Inverzincins
Authors: Maskos Klaus 
Published: April 2006

AbstractInverzincins are characterized by an inverted zinc‐binding motif (HxxEH) rather than the classical zincin motif (HExxH). Pitrilysin fromEscherichia coliis the prototype of one subfamily, which also contains eukaryotic family members such as the insulin‐degrading enzyme (IDE) and theN‐arginine dibasic convertase (NRDc), both playing important roles in hormone metabolism and cellular regulation. The topology of active site residues shows some similarity to zincins, suggesting a convergent evolution for these types of metalloproteases. The closely related members of the mitochondrial processing peptidase (MPP) subfamily function as soluble heterodimers or as building blocks of the cytochrome c reductase complex and share the tendency with pitrilysin‐like enzymes to cleave peptides at hydrophobic or positively charged sites in a context‐dependent manner. For several family members, binding and cleavage of substrate is supposed to depend on secondary or tertiary structure and seems to proceed within a compartment formed by the respective enzyme.
Bacillus SubtilisD‐AminopeptidaseDppA
Authors: Remaut Han , Goffin Colette , Frère Jean‐Marie , Beeumen Jozef Van 
Published: April 2006

AbstractTheD‐aminopeptidase DppA, identified inBacillusspecies, represents the prototype of a separate family of dinuclear zinc proteases. The catalytic domain of the enzyme comprises a Rossmann‐like α/β/α‐fold that coordinates two zinc ions near the C‐terminal edge of a six‐stranded parallel β‐sheet. Despite the lack in sequence and structural homology, the zinc coordination is highly similar to that found in established dinuclear zinc proteases. Furthermore, DppA forms a decameric molecule that encloses a central cavity that sequesters the 10 active sites. The architecture of the complex strongly resembles that found in a group of enzymes known as self‐compartmentalizing proteases, with bacterial and eukaryotic proteasomes as most characteristic examples.
Calmodulin
Authors: Yap Kyoko L , Ikura Mitsuhiko 
Published: April 2006

AbstractCaM is a ubiquitous eukaryotic calcium binding protein that interacts with hundreds of proteins including kinases and phosphatases, transmembrane ion channels and pumps, and cytoskeletal regulatory proteins. In response to an increase in intracellular calcium, CaM undergoes a major conformational change enabling target binding and activation. In some cases, CaM is able to bind target proteins in the absence of, or independently of, Ca2+; in others, CaM binding may induce inactivation. The structural plasticity of calmodulin is demonstrated by the diversity observed in its interaction with various targets.
Troponin
C
Authors: Gagné Stéphane M 
Published: April 2006

Abstract
Regulation of contraction in skeletal and cardiac muscle occurs through calcium binding to the protein troponin C (TnC). The N‐terminal domain of TnC (NTnC) carries out the regulatory role through the binding of calcium ions – two calcium ions in skeletal muscle and one in cardiac muscle.
Thirty‐nine sequences of TnC have been sequenced so far. Of the 39 sequences of TnC, 5 have had their three‐dimensional structures determined in various forms by NMR and X‐ray. Available structures include 26 uncomplexed structures in various calcium states, and 13 structures in which cardiac and skeletal TnC is complexed with fragments of troponin I and/or troponin T.
Gating Domain of Calcium‐Activated Potassium Channel with Calcium and Calmodulin
Authors: Schumacher Maria A 
Published: April 2006

AbstractSmall conductance Ca2+‐activated K+channels (SK channels) are voltage‐independent and gated solely by increases in intracellular Ca2+such as that occurs during an action potential. SK channels are heteromeric complexes and consist of pore‐forming α‐subunits and calmodulin (CaM). CaM is constitutively associated with an intracellular region of the α‐subunit immediately C‐terminal to the pore, the CaM binding domain (CaMBD). In order to trigger channel opening, Ca2+must only bind the EF hands in the CaM N‐lobe. The 1.60‐Å crystal structure of the SK channel Ca2+/CaM/CaMBD complex reveals that the CaMBD forms an elongated dimer with a CaM bound at each end and each CaM wraps around three α‐helices, two from one CaMBD subunit and one from the other. The structure also provides a view of both Ca2+‐dependent and Ca2+‐independent protein interactions; only the CaM N‐lobe is calcified while the noncalcified C‐lobe is responsible for the CaM/CaMBD constitutive interaction. This structure combined with biochemical data suggests a possible gating mechanism in which Ca2+binding to each CaM N‐lobe exposes its hydrophobic patch, thus allowing it to interact with an adjacent CaMBD monomer. As each N‐lobe on adjacent monomers interacts with the other CaMBD C‐terminal region, a rotary force would be created between them and transmitted to the attached S6 pore helices in the gate region. In this chemo‐mechanical model, two CaMBD dimers would serve as mechanical levers to drive open the channel.
Basement Membrane Protein
BM
‐40
Authors: Hohenester Erhard , Timpl Rupert 
Published: April 2006

Abstract

BM‐40, also known as SPARC or osteonectin, is a secreted glycoprotein present in all metazoa. The protein is expressed in tissues undergoing morphogenesis, remodeling, and repair.
In vitro
, BM‐40 binds to several collagens and is both antiproliferative and counteradhesive. Human BM‐40 consists of an acidic N‐terminal domain, a follistatin‐like (FS) domain, and an α‐helical (EC) domain that contains two functional EF‐hand calcium‐binding motifs. The crystal structure of the FS–EC domain pair has been determined. Calcium and collagen binding to the EC domain has been studied using site‐directed mutagenesis, spectroscopy, and binding assays.