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Architecture and regulation of HtrA-family proteins involved in protein quality control and stress response

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Abstract

Protein quality control is vital for all living cells and sophisticated molecular mechanisms have evolved to prevent the excessive accumulation of unfolded proteins. High-temperature requirement A (HtrA) proteases have been identified as important ATP-independent quality-control factors in most species. HtrA proteins harbor a serine-protease domain and at least one peptide-binding PDZ domain to ensure efficient removal of misfolded or damaged proteins. One distinctive property of HtrAs is their ability to assemble into complex oligomers. Whereas all examined HtrAs are capable of forming pyramidal 3-mers, higher-order complexes consisting of up to 24 molecules have been reported. Tight control of chaperone and protease function is of pivotal importance in preventing deleterious HtrA-protease activity. In recent years, structural biology provided detailed insights into the molecular basis of the regulatory mechanisms, which include unique intramolecular allosteric signaling cascades and the dynamic switching of oligomeric states of HtrA proteins. Based on these results, functional models for many family members have been developed. The HtrA protein family represents a remarkable example of how structural and functional diversity is attained from the assembly of simple molecular building blocks.

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Abbreviations

ADAM9:

A disintegrin and metalloproteinase domain-containing 9

FRET:

Förster resonance energy transfer

HtrA:

High-temperature requirement A

OMP:

Outer membrane protein

PDZ:

Postsynaptic density of 95 kDa (PSD-95), discs large (DLG1), and zonula occludens 1 (ZO-1)

rmsd:

Root-mean-square deviation

SEC:

Size-exclusion chromatography

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Acknowledgments

We thank Sen-Fang Sui and Xiaochen Bai for supplying the atomic coordinates of DegQEc models based on their cryo-EM data. RH is supported by a Chinese Academy of Sciences Visiting Professorship for Senior International Scientists, Grant no. 2010T1S6, by the DFG Cluster of Excellence “Inflammation at Interfaces” (EXC 306), as well as by the Fonds der Chemischen Industrie.

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Authors and Affiliations

  1. Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538, Lübeck, Germany

    Guido Hansen & Rolf Hilgenfeld

  2. German Centre for Infection Research (DZIF), University of Lübeck, Lübeck, Germany

    Guido Hansen & Rolf Hilgenfeld

  3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Rd., Shanghai, 201203, China

    Rolf Hilgenfeld

  4. Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, Building 22a, 22603, Hamburg, Germany

    Rolf Hilgenfeld

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Correspondence to Guido Hansen.

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Hansen, G., Hilgenfeld, R. Architecture and regulation of HtrA-family proteins involved in protein quality control and stress response. Cell. Mol. Life Sci. 70, 761–775 (2013). https://doi.org/10.1007/s00018-012-1076-4

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