New HEAT-like repeat motifs in proteins regulating proteasome structure and function

Kajava, Andrey V.; Gorbea, Carlos; Rechsteiner, Martin; Steven, Alasdair C.

doi:10.1016/j.jsb.2004.01.013

Cited by 71 publications

(73 citation statements)

References 34 publications

(44 reference statements)

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“…1 are bona fide Ecm29-binding partners and, furthermore, to believe that their association with Ecm29 serves important physiological functions. First, Ecm29 is a large protein that contains numerous HEAT repeats (30,33); these structural elements are present in other adaptor proteins. For example, Huntingtin, a founding member of the HEAT-repeat protein family, interacts with an equally diverse set of proteins (62,63).…”

Section: Discussionmentioning

confidence: 99%

“…Ecm29 has been reasonably conserved during evolution, and all Ecm29 sequences are predicted to consist of numerous HEAT repeats, secondary structural motifs often present in proteins that function as adaptors (33,34). Consistent with a possible adaptor function for Ecm29, Ecm proteasomes are localized on the endoplasmic reticulum (ER), on endosomes and at the centrosome in HeLa cells; based on its intracellular distribution we proposed that Ecm29 links 26 S proteasomes to these cellular compartments (30).…”

mentioning

confidence: 89%

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A Protein Interaction Network for Ecm29 Links the 26 S Proteasome to Molecular Motors and Endosomal Components

Gorbea

Pratt

Ustrell

et al. 2010

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

A Protein Interaction Network for Ecm29 Links the 26 S Proteasome to Molecular Motors and Endosomal Components

Gorbea

Pratt

Ustrell

et al. 2010

Journal of Biological Chemistry

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“…14 The PA200 sequence contains multiple HEAT-like repeats suggesting that the protein adopts a solenoid structure. 15 The sequences of PA200 and the yeast Blm10 (formerly known as Blm3 16,17 ) proteins are 20% identical (41% similar) over the 1715 C-terminal residues of each protein. Conservation of this class of proteasome activators from yeast to humans suggests an important and evolutionary conserved biological role.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the map is consistent with the solenoid predicted by the presence of multiple HEAT-like repeats in the Blm10 sequence. 15 We also describe genetic experiments to investigate the role of Blm10 in DNA damage repair and in growth at high temperatures. In contrast to earlier reports, 17,18,19 our results do not support a significant role for Blm10 in DNA damage repair or resistance to stresses that cause misfolding of proteins.…”

Section: Introductionmentioning

confidence: 99%

Structure of the Blm10–20 S Proteasome Complex by Cryo-electron Microscopy. Insights into the Mechanism of Activation of Mature Yeast Proteasomes

Iwanczyk

Sadre-Bazzaz

Ferrell

et al. 2006

Journal of Molecular Biology

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The 20S proteasome is regulated at multiple levels including association with endogenous activators. Two activators have been described for the yeast 20S proteasome: the 19S regulatory particle and the Blm10 protein. The sequence of Blm10 is 20% identical to the mammalian PA200 protein. Recent studies have shown that the sequences of Blm10 and PA200 each contain multiple HEAT-repeats and that each binds to the ends of mature proteasomes, suggesting a common structural and biochemical function. In order to advance structural studies, we have developed an efficient purification method that produces high yields of stoichiometric Blm10-mature yeast 20S proteasome complexes and we constructed a three-dimensional (3D) model of the Blm10-20S complex from cryo-electron microscopy images. This reconstruction shows that Blm10 binds in a defined orientation to both ends of the 20S particle and contacts all the proteasome α subunits. Blm10 displays the solenoid folding predicted by the presence of multiple HEAT-like repeats and the axial gates on the α rings of the proteasome appear to be open in the complex. We also performed a genetic analysis in an effort to identify the physiological role of Blm10. These experiments, however, did not reveal a robust phenotype upon gene deletion, overexpression, or in a screen for synthetic effects. This leaves the physiological role of Blm10 unresolved, but challenges earlier findings of a role in DNA repair.

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“…PA200 is an evolutionarily conserved, nuclear localized, multiple HEAT-repeat protein that associates with the ends of mature 20S proteasomes and enhances peptide hydrolysis, most notably after acidic residues (postglutamyl cleavage) in vitro (4,17,18). Both mammalian PA200 and its ortholog in Saccharomyces cerevisiae (known as Blm10) are reported to form hybrid proteasomes consisting of one 19S cap on one end and one Blm10/PA200 cap on the other end of a core proteasome (4,19).…”

mentioning

confidence: 99%

Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability

Blickwedehl

Agarwal

Seong

et al. 2008

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

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Proteasome activator PA200 enhances proteasome-mediated cleavage after acidic residues in vitro; however, its role within cells is not known. Here, we show that, in response to ionizing radiation, PA200 forms hybrid proteasomes with 19S caps and 20S core proteasomes that accumulate on chromatin, leading to an increase in proteolytic activity. Unlike many other proteins that respond to DNA damage, the response of PA200 appears to be independent of Ataxia Telangiectasia Mutated and p53, but dependent on DNAdependent protein kinase activity. Nonetheless, PA200 is critical because PA200-knockdown cells show genomic instability and reduced survival after exposure to ionizing radiation. This phenotype is reproduced by specific inhibition of postglutamyl activity of proteasomes, but combined treatment with PA200 siRNA and postglutamyl inhibitor does not show additive effects on survival. Together, these data suggest a unique role for PA200 in genomic stability that is likely mediated through its ability to enhance postglutamyl cleavage by proteasomes.ATM ͉ chromatin ͉ DNA-dependent protein kinase ͉ ionizing radiation ͉ DNA damage

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New HEAT-like repeat motifs in proteins regulating proteasome structure and function

Cited by 71 publications

References 34 publications

A Protein Interaction Network for Ecm29 Links the 26 S Proteasome to Molecular Motors and Endosomal Components

A Protein Interaction Network for Ecm29 Links the 26 S Proteasome to Molecular Motors and Endosomal Components

Structure of the Blm10–20 S Proteasome Complex by Cryo-electron Microscopy. Insights into the Mechanism of Activation of Mature Yeast Proteasomes

Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability

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