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1.
Hypertens Res ; 39(7): 492-500, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26888118

RESUMO

Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides. Although AGT is generally considered as a passive substrate of the renin-angiotensin system, there is accumulating evidence that the regulation and functions of AGT are intricate. Understanding the diversity of AGT properties has been enhanced by protein structural analysis and animal studies. In addition to whole-body genetic deletion, AGT can be regulated in vivo by cell-specific procedures, adeno-associated viral approaches and antisense oligonucleotides. Indeed, the availability of these multiple manipulations of AGT in vivo has provided new insights into the multifaceted roles of AGT. In this review, the combination of structural and functional studies is highlighted to focus on the increasing recognition that AGT exerts effects beyond being a sole provider of angiotensin peptides.


Assuntos
Angiotensinogênio , Angiotensinogênio/química , Angiotensinogênio/genética , Angiotensinogênio/farmacocinética , Animais , Aterosclerose/metabolismo , Pressão Sanguínea , Sequência Conservada , Fígado Gorduroso/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Obesidade/metabolismo , Renina/genética , Renina/farmacocinética , Sistema Renina-Angiotensina/fisiologia , Relação Estrutura-Atividade
2.
Nat Struct Mol Biol ; 18(2): 198-204, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21240271

RESUMO

Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates. We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents.


Assuntos
Integrinas/metabolismo , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/química , Pirofosfatases/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Cristalografia por Raios X , Humanos , Lisofosfolipídeos/metabolismo , Dados de Sequência Molecular , Mutação , Diester Fosfórico Hidrolases/genética , Ligação Proteica , Estrutura Terciária de Proteína , Pirofosfatases/genética , Ratos , Especificidade por Substrato
3.
Biochemistry ; 46(23): 6957-70, 2007 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-17508727

RESUMO

The receptor for advanced glycation end products (RAGE) is an important cell surface receptor being pursued as a therapeutic target because it has been implicated in complications arising from diabetes and chronic inflammatory conditions. RAGE is a single membrane spanning receptor containing a very small approximately 40 residue cytosolic domain and a large extracellular region composed of 3 Ig-like domains. In this study, high level bacterial expression systems and purification protocols were generated for the extracellular region of RAGE (sRAGE) and the five permutations of single and tandem domain constructs to enable biophysical and structural characterization of its tertiary and quaternary structure. The structure and stability of each of these six protein constructs was assayed by biochemical methods including limited proteolysis, dynamic light scattering, CD, and NMR. A homology model of sRAGE was constructed to aid in the interpretation of the experimental data. Our results show that the V and C1 domains are not independent domains, but rather form an integrated structural unit. In contrast, C2 is attached to VC1 by a flexible linker and is fully independent. The interaction with a known RAGE ligand, Ca2+-S100B, was mapped to VC1, with the major contribution from the V domain but clearly defined secondary effects from the C1 domain. The implications of these results are discussed with respect to models for RAGE signaling.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Receptores Imunológicos/química , Receptores Imunológicos/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA/química , DNA/genética , Escherichia coli/genética , Produtos Finais de Glicação Avançada/química , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Conformação Proteica , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
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