ClpL ATPase: A Novel Chaperone in Bacterial Stress Responses

Khara, Pratick; Biswas, Indranil

doi:10.1002/9781119004813.ch78

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(4 citation statements)

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“…While our results indicate that molecular functions of ClpL are different from those of the other well-studied chaperones such as ClpB, we also noticed that the behavior of ClpL of S. mutans is different from that of ClpL of S. pneumoniae . For example, ClpL of S. mutans exists as a trimer in solution whereas ClpL of S. pneumoniae exists as a monomer .…”

Section: Discussioncontrasting

confidence: 69%

“…Streptococcus mutans is a low-GC Gram-positive oral bacterium associated with dental caries formation in humans. It also harbors a chromosomally encoded ClpL homologue that is induced during various stresses . A S. mutans strain lacking a functional ClpL displays an acid-shock response and increased sensitivity to some antibiotics; however, its exact molecular function is currently unknown.…”

mentioning

confidence: 99%

“…It also harbors a chromosomally encoded ClpL homologue that is induced during various stresses . A S. mutans strain lacking a functional ClpL displays an acid-shock response and increased sensitivity to some antibiotics; however, its exact molecular function is currently unknown. S. mutans ClpL is highly homologous to its counterpart from Streptococcus pneumoniae and Streptococcus thermophilus . , ClpL is required for virulence expression and antibiotic resistance in S. pneumoniae , and in acid tolerance in S. thermophilus .…”

mentioning

confidence: 99%

“…We recently determined that in S. mutans ClpL acts as a chaperone to properly fold CtsR, a stress response repressor, and prevents it from forming protein aggregates . We showed that ClpL could successfully refold urea-denatured CtsR but not aggregated proteins and proposed that ClpL recognizes primarily soluble but denatured substrates and prevents the formation of large protein aggregates. , Recently, it was shown that ClpL of S. pneumoniae also functions as a chaperone and can refold heterologous proteins in vitro . In this study, we wanted to further explore the biochemical functions of the S. mutans ClpL protein to gain insights into its molecular roles.…”

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confidence: 99%

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Significance of Individual Domains of ClpL: A Novel Chaperone from Streptococcus mutans

Jana

Biswas

2020

Biochemistry

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ClpL is a member of the HSP100 family of the AAA+ chaperone that is widely present in Grampositive but surprisingly absent in Gram-negative bacteria. ClpL is involved in various cellular processes including stress tolerance response, long-term survival, virulence, and antibiotic resistance. ClpL is poorly characterized and its molecular mechanisms of chaperone activity are largely unclear. Here, we biochemically characterized the ClpL protein from Streptococcus mutans, a dental pathogen, to understand its biological functions. ClpL harbors five domains: Ndomain, two nucleotide binding domains (NBD-1 and NBD-2), M-domain, and C-domain. NBD-1 and NBD-2 contain distinct Walker A and B motifs for ATP binding and hydrolysis, respectively. We found that ClpL predominantly exists as a trimer in solution; however, upon ATP binding, it rapidly forms a hexameric structure. To study structure-function activity, we constructed several substitution and deletion mutants. We found that mutations in Walker A and B motifs interfered with the ATP hydrolysis and oligomerization. Similarly, deletions of N-, M-, and C-domains abolished both the ATPase activity and oligomerization. Since we previously found that ClpL acts as a chaperone, we analyzed the chaperone activity. Surprisingly, we found that the NBD-2 mutants did not display any chaperone activity indicating the essentiality of ATP binding and hydrolysis by NBD-2 for chaperone. However, NBD-1 mutants showed chaperone activities, but the activities were variable depending on the nature of the mutations. Our results indicate that unlike other HSP100 family chaperones, ClpL is a novel chaperone that does not require any additional secondary chaperones for its activity.

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Section: Discussioncontrasting

confidence: 69%

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confidence: 99%