Crystal Structure of Skp, a Prefoldin-like Chaperone that Protects Soluble and Membrane Proteins from Aggregation

Walton, Troy A.; Sousa, Marcelo C.

doi:10.1016/j.molcel.2004.07.023

Cited by 196 publications

(229 citation statements)

References 37 publications

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“…1A) (8,9). The Skp structure was unexpectedly similar to that of prefoldin, a cytosolic molecular chaperone present in archea and eukarya (8)(9)(10). Although Skp is a trimer (8,9,11) and prefoldin is a hexamer (12,13), both proteins share jellyfish architectures with a central cavity ( Fig.…”

mentioning

confidence: 86%

“…Previous studies have shown that Skp can prevent the aggregation of model proteins like lysozyme (8). We next wanted to test Skp function with a true OMP substrate.…”

Section: Skp Prevents the Aggregation Of Ompa By Forming A Stable Commentioning

confidence: 99%

“…The crystal structure of Skp revealed a trimer with a ''jellyfish'' architecture where a central cavity is formed by long tentacle-like helical protrusions emanating from a body domain (Fig. 1A) (8,9). The Skp structure was unexpectedly similar to that of prefoldin, a cytosolic molecular chaperone present in archea and eukarya (8)(9)(10).…”

mentioning

confidence: 93%

“…OMPs have to cross the inner membrane and the aqueous periplasmic space before they are inserted in the outer membrane (18). Skp is thought to bind OMPs as they emerge from the translocation machinery in the inner membrane, protect them from aggregation in the periplasm, and deliver them to the outer membrane in a state competent for insertion (8,18,19). However, the molecular mechanism remains unclear.…”

mentioning

confidence: 99%

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The cavity-chaperone Skp protects its substrate from aggregation but allows independent folding of substrate domains

Walton

Sandoval

Fowler

et al. 2009

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

114

116

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Outer membrane proteins (OMPs) of Gram-negative bacteria are synthesized in the cytosol and must cross the periplasm before insertion into the outer membrane. The 17-kDa protein (Skp) is a periplasmic chaperone that assists the folding and insertion of many OMPs, including OmpA, a model OMP with a membrane embedded ␤-barrel domain and a periplasmic ␣␤ domain. Structurally, Skp belongs to a family of cavity-containing chaperones that bind their substrates in the cavity, protecting them from aggregation. However, some substrates, such as OmpA, exceed the capacity of the chaperone cavity, posing a mechanistic challenge. Here, we provide direct NMR evidence that, while bound to Skp, the ␤-barrel domain of OmpA is maintained in an unfolded state, whereas the periplasmic domain is folded in its native conformation. Complementary cross-linking and NMR relaxation experiments show that the OmpA ␤-barrel is bound deep within the Skp cavity, whereas the folded periplasmic domain protrudes outside of the cavity where it tumbles independently from the rest of the complex. This domain-based chaperoning mechanism allows the transport of ␤-barrels across the periplasm in an unfolded state, which may be important for efficient insertion into the outer membrane.cavity-based ͉ outer membrane M any molecular chaperones have evolved cavity-like structures to bind their non-native substrates. Classic examples, such as the chaperonins, bind the substrate in the cavity formed by their open rings and protect them from aggregation. Cycles of ATP binding and hydrolysis, coupled with substrate binding and release, then help the substrate achieve its native conformation (1). Because the cavities of these chaperones have limited capacities, binding substrates larger than the cavity requires a portion of the substrate to be bound inside the cavity while the rest of the substrate remains outside. In these cases, however, the entire substrate remains unfolded while bound to the open ring of the chaperone (2-4).The 17-kDa protein (Skp) is a periplasmic chaperone present in many Gram-negative bacteria involved in the folding and insertion of proteins in the outer membrane (5-7). The crystal structure of Skp revealed a trimer with a ''jellyfish'' architecture where a central cavity is formed by long tentacle-like helical protrusions emanating from a body domain (Fig. 1A) (8, 9). The Skp structure was unexpectedly similar to that of prefoldin, a cytosolic molecular chaperone present in archea and eukarya (8-10). Although Skp is a trimer (8, 9, 11) and prefoldin is a hexamer (12, 13), both proteins share jellyfish architectures with a central cavity ( Fig. 1 A and B). In prefoldin, this cavity has been shown to bind substrate proteins (10, 13). Prefoldin thus belongs to a family of chaperones sometimes referred to as ''holdases.'' These chaperones are ATP independent and, in contrast to chaperonins, do not directly facilitate folding of their substrates. Instead they protect the substrates from aggregation by holding them in their cavities, and subs...

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mentioning

confidence: 86%

“…Previous studies have shown that Skp can prevent the aggregation of model proteins like lysozyme (8). We next wanted to test Skp function with a true OMP substrate.…”

Section: Skp Prevents the Aggregation Of Ompa By Forming A Stable Commentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

See 2 more Smart Citations

The cavity-chaperone Skp protects its substrate from aggregation but allows independent folding of substrate domains

Walton

Sandoval

Fowler

et al. 2009

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

114

116

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“…Crystal structures are also available for the cytosolic chaperone prefoldin and the bacterial periplasmic chaperone Skp, and these reveal a strikingly similar overall architecture given that the proteins have no evolutionary relationship (32)(33)(34)(35). Prefoldin is a 90 kDa complex of two a and four b subunits present in the cytosol of eukaryotes and archea (36, 37) (Fig.…”

Section: Structure Of the Small Tim Chaperonesmentioning

confidence: 99%

Mitochondrial ATP‐independent chaperones

2009

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SummaryMitochondria possess a dedicated-chaperone system in the intermembrane space, the small Tims that are ubiquitous in all eukaryotes from yeast to man. They escort membrane proteins to the outer or the inner membrane for proper insertion. These mitochondrial chaperones do not require external energy to perform their function and have structural similarities to other ATP-independent chaperones. Here, we discuss their structural properties and how these relate to their chaperoning function in the mitochondrial intermembrane space.

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Folding and Stability of Monomeric β‐Barrel Membrane Proteins

Kleinschmidt¹

2005

Protein–Lipid Interactions

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Crystal Structure of Skp, a Prefoldin-like Chaperone that Protects Soluble and Membrane Proteins from Aggregation

Cited by 196 publications

References 37 publications

The cavity-chaperone Skp protects its substrate from aggregation but allows independent folding of substrate domains

The cavity-chaperone Skp protects its substrate from aggregation but allows independent folding of substrate domains

Mitochondrial ATP‐independent chaperones

Folding and Stability of Monomeric β‐Barrel Membrane Proteins

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