A Three-part Signal Governs Differential Processing of Gli1 and Gli3 Proteins by the Proteasome

Schrader, Erin K.; Harstad, Kristine G.; Holmgren, Robert A.; Matouschek, Andreas T

doi:10.1074/jbc.m111.274993

Cited by 32 publications

(33 citation statements)

References 51 publications

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“…3H). Taken together with the previous results, we conclude that the natural partial processing of DnaX requires both a tightly folded domain and a glycine-rich region, similar to those requirements for the 26S proteasome (28,29). We note that because DnaXnp is degraded slowly, it is possible that partial fragments of DnaXnp are transiently generated but are degraded so rapidly relative to full-length protein that they are undetectable by our methods.…”

Section: Partial Processing Of Dnax Requires Folded Domains Adjacent Tosupporting

confidence: 85%

“…3A). Interestingly, the 26S proteasome is known to stall at glycine-rich regions during ubiquitin-mediated proteolysis if those regions are adjacent to tightly folded domains (28,29), and more recently, a similar effect has been shown with engineered substrates of ClpXP in vitro (30). We addressed if processing of DnaX followed similar rules by generating a construct containing residues 317-608 that removes the oligomerizing N-terminal domains of DnaX (31) but preserves the glycine-rich region and residues 535-557, which are critical for ClpXP degradation.…”

Section: Partial Processing Of Dnax Requires Folded Domains Adjacent Tomentioning

confidence: 99%

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Critical clamp loader processing by an essential AAA+ protease in Caulobacter crescentus

Vass

Chien

2013

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

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Chromosome replication relies on sliding clamps that are loaded by energy-dependent complexes. In Escherichia coli, the ATP-binding clamp loader subunit DnaX exists as both long (τ) and short (γ) forms generated through programmed translational frameshifting, but the need for both forms is unclear. Here, we show that in Caulobacter crescentus, DnaX isoforms are unexpectedly generated through partial proteolysis by the AAA+ protease casein lytic proteinase (Clp) XP. We find that the normally processive ClpXP protease partially degrades DnaX to produce stable fragments upon encountering a glycine-rich region adjacent to a structured domain. Increasing the sequence complexity of this region prevents partial proteolysis and generates a τ-only form of DnaX in vivo that is unable to support viability on its own. Growth is restored when γ is provided in trans, but these strains are more sensitive to DNA damage compared with strains that can generate γ through proteolysis. Our work reveals an unexpected mode of partial processing by the ClpXP protease to generate DnaX isoforms, demonstrates that both τ and γ forms of DnaX are required for Caulobacter viability, and identifies a role for clamp loader diversity in responding to DNA damage. The conservation of distinct DnaX isoforms throughout bacteria despite fundamentally different mechanisms for producing them suggests there may be a conserved need for alternate clamp loader complexes during DNA damaging conditions. protease stalling | ClpP | ClpX internal recognition

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Section: Partial Processing Of Dnax Requires Folded Domains Adjacent Tosupporting

confidence: 85%

Section: Partial Processing Of Dnax Requires Folded Domains Adjacent Tomentioning

confidence: 99%

Critical clamp loader processing by an essential AAA+ protease in Caulobacter crescentus

Vass

Chien

2013

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

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“…The ubiquitin-proteasome system modulates Gli2 and Gli3 activity in two ways: it completely degrades the fully activated transcription factors in the presence of Hh and partially degrades Gli2 and Gli3 to convert them to repressors in the absence of Hh [116]. While the most common function of the proteasome is to degrade proteins completely, partial processing occurs when the proteasome runs into a folded domain that stalls its progress along the polypeptide, giving the remainder of the protein a chance to escape degradation.…”

Section: Partial Degradation Of Gli2 and Gli3mentioning

confidence: 99%

“…Transplanting the PDD of Gli3 into Gli2 was able to transfer the ability to be processed efficiently. However, it was later established that the PDD was not sufficient to induce partial proteasomal degradation of Gli1, and further studies revealed that the processing signal is encoded in three distinct regions of Gli3: the Zn-finger domain, a linker region, and a degron sequence [116].…”

Section: Partial Degradation Of Gli2 and Gli3mentioning

confidence: 99%

Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins

Riobó

2014

Topics in Medicinal Chemistry

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The Hedgehog (Hh) signaling pathway has received a great deal of attention in the past decade due to its involvement in cancer, angiogenesis, and fibrosis. Several inhibitors of the pathway were developed which target the 7-transmembrane protein Smoothened (Smo), core component of the canonical pathway that controls Gli-dependent transcriptional activity. However, recent studies revealed that the Hh pathway has other transcription-independent functions, collectively known as "non-canonical signaling." This review describes the role and function of each Hh pathway component in canonical and non-canonical signaling, with emphasis on the role of Smo as a GPCR that selectively activates heterotrimeric G i proteins.

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“…The increased efficiency of Gli3 processing is due in large part to the sequence of a 200-residue processing determinant domain in its C terminus (79). Together with an appropriate degron and the zinc finger domain, the processing determinant domain forms a three-part signal that is essential for efficient Gli3 processing (80). But what happens to Gli2-FL in the absence of Hh?…”

Section: Transcriptional Repression In Absence Of Hedgehogmentioning

confidence: 99%

Hedgehog Secretion and Signal Transduction in Vertebrates

Ryan

Chiang

2012

Journal of Biological Chemistry

107

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Signaling by the Hedgehog (Hh) family of secreted proteins is essential for proper embryonic patterning and development. Dysregulation of Hh signaling is associated with a variety of human diseases ranging from developmental disorders such as holoprosencephaly to certain forms of cancer, including medulloblastoma and basal cell carcinoma. Genetic studies in flies and mice have shaped our understanding of Hh signaling and revealed that nearly all core components of the pathway are highly conserved. Although many aspects of the Drosophila Hh pathway are conserved in vertebrates, mechanistic differences between the two species have begun to emerge. Perhaps the most striking divergence in vertebrate Hh signaling is its dependence on the primary cilium, a vestigial organelle that is largely absent in flies. This minireview will provide an overview of Hh signaling and present recent insights into vertebrate Hh secretion, receptor binding, and signal transduction.

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A Three-part Signal Governs Differential Processing of Gli1 and Gli3 Proteins by the Proteasome

Cited by 32 publications

References 51 publications

Critical clamp loader processing by an essential AAA+ protease in Caulobacter crescentus

Critical clamp loader processing by an essential AAA+ protease in Caulobacter crescentus

Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins

Hedgehog Secretion and Signal Transduction in Vertebrates

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