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H Grallert

Publications and source records attributed to H Grallert.

6 recordsLinked to original sources
PubMed2007

Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys.

Recently, significant associations between common variants of the transcription factor 7-like 2 gene ( TCF7L2) and type 2 diabetes have been reported. This study was designed to replicate the reported associations of the two highly correlated (r (2)=0.86) TCF7L2 single nucleotide polymorphisms rs12255372 and rs7903146 with type 2 diabetes in a case-control study of 2369 MONICA/KORA participants (678 cases/1691 controls from Augsburg, Germany). To further investigate the pathogenic mechanism underlying these associations, we extended our analyses to the metabolic syndrome (IDF, NCEP definitions) and its components in a population-based study comprising 1404 male and female KORA participants aged 55-74 years. Results of our analyses strongly confirmed the minor T alleles as risk variants for type 2 diabetes (rs7903146: OR (TvsC) [95% CI]=1.36 [1.18;1.58], p=0.00003, and rs12255372: OR (TvsG) [95% CI]=1.31 [1.13;1.51], p=0.0003). Moreover, the T allele at rs7903146 was inversely associated with log-transformed, HOMA-%B (beta=-0.07, p=0.005) as a measure of basal insulin secretion, and log-transformed fasting insulin (beta=-0.06, p=0.02). No association was found with insulin resistance (HOMA-IR) and the metabolic syndrome. These findings support replication evidence that TCF7L2 variants increase type 2 diabetes risk. TCF7L2 may primarily affect pancreatic beta cell function.

Aged↗
PubMed2001

Review: a structural view of the GroE chaperone cycle.

The GroE chaperone system consists of two ring-shaped oligomeric components whose association creates different functional states. The most remarkable property of the GroE system is the ability to fold proteins under conditions where spontaneous folding cannot occur. To achieve this, a fully functional system consisting of GroEL, the cochaperone GroES, and ATP is necessary. Driven by ATP binding and hydrolysis, this system cycles through different conformational stages, which allow binding, folding, and release of substrate proteins. Some aspects of the ATP-driven reaction cycle are still under debate. One of these open questions is the importance of so-called "football" complexes consisting of GroEL and two bound GroES rings. Here, we summarize the evidence for the functional relevance of these complexes and their involvement in the efficient folding of substrate proteins.

Adenosine Triphosphate↗
PubMed2000

Limits of protein folding inside GroE complexes.

The GroE chaperones of Escherichia coli promote the folding of other proteins under conditions where no spontaneous folding occurs. One requirement for this reaction is the trapping of the nonnative protein inside the chaperone complex. Encapsulation may be important to prevent unfavorable intermolecular interactions during folding. We show here that, especially for oligomeric proteins, the timing of encapsulation and release is of critical importance. If this cycle is decelerated, misfolding is observed inside functional chaperone complexes.

Adenosine Triphosphatases↗
PubMed1999

Analysis of GroE-assisted folding under nonpermissive conditions.

The molecular chaperones GroEL and GroES facilitate protein folding in an ATP-dependent manner under conditions where no spontaneous folding occurs. It has remained unknown whether GroE achieves this by a passive sequestration of protein inside the GroE cavity or by changing the folding pathway of a protein. Here we used citrate synthase, a well studied model substrate, to discriminate between these possibilities. We demonstrate that GroE maintains unfolding intermediates in a state that allows productive folding under nonpermissive conditions. During encapsulation of non-native protein inside GroEL.GroES complexes, a folding reaction takes place, generating association-competent monomeric intermediates that are no longer recognized by GroEL. Thus, GroE shifts folding intermediates to a productive folding pathway under heat shock conditions where even the native protein unfolds in the absence of GroE.

Chaperonin 10↗
PubMed1998

GroEL traps dimeric and monomeric unfolding intermediates of citrate synthase.

The prokaryotic molecular chaperone GroE is increasingly expressed under heat shock conditions. GroE protects cells by preventing the irreversible aggregation of thermally unfolding proteins. Here, the interaction of GroE with thermally unfolding citrate synthase (CS) was dissected into several steps that occur before irreversible aggregation, and the conformational states of the unfolding protein recognized by GroEL were determined. The kinetic analysis of CS unfolding revealed the formation of inactive dimeric and monomeric intermediates. GroEL binds both intermediates without affecting the unfolding pathway. Furthermore, the dimeric intermediates are not protected against dissociation in the presence of GroEL. Monomeric CS is stably associated with GroEL, thus preventing further irreversible unfolding steps and subsequent aggregation. During refolding, monomeric CS is encapsulated inside the cavity of GroEL. GroES complexes. Taken together our results suggest that for protection of cells against heat stress both the ability of GroEL to interact with a large variety of nonnative conformations of proteins and the active, GroES-dependent refolding of highly unfolded species are important.

Binding Sites↗