Molecular basis of Tousled-Like Kinase 2 activation

Gulnahar B. Mortuza; Dario Hermida; Anna-Kathrine Pedersen; Sandra Segura-Bayona; Blanca López-Méndez; Pilar Redondo; Patrick Rüther; Irina Pozdnyakova; Ana M Garrote; Inés G Muñoz; Marina Villamor-Payà; Cristina Jauset; Jesper V. Olsen; Travis H. Stracker; Guillermo Montoya

doi:10.1038/s41467-018-04941-y

Molecular basis of Tousled-Like Kinase 2 activation

Gulnahar B. Mortuza, Dario Hermida, Anna-Kathrine Pedersen, Sandra Segura-Bayona, Blanca López-Méndez, Pilar Redondo, Patrick Rüther, Irina Pozdnyakova, Ana M Garrote, Inés G Muñoz, Marina Villamor-Payà, Cristina Jauset, Jesper V. Olsen, Travis H. Stracker, Guillermo Montoya

Protein Structure and Function Program

8 Citationer (Scopus)

77 Downloads (Pure)

Abstract

Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.

Originalsprog	Engelsk
Artikelnummer	2535
Tidsskrift	Nature Communications
Vol/bind	9
Udgave nummer	1
Sider (fra-til)	2535
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-018-04941-y
Status	Udgivet - 2018

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1038/s41467-018-04941-y

Molecular basis of Tousled-Like Kinase 2 activationForlagets udgivne version, 2,65 MB

Citationsformater

Mortuza, G. B., Hermida, D., Pedersen, A.-K., Segura-Bayona, S., López-Méndez, B., Redondo, P., Rüther, P., Pozdnyakova, I., Garrote, A. M., Muñoz, I. G., Villamor-Payà, M., Jauset, C., Olsen, J. V., Stracker, T. H., & Montoya, G. (2018). Molecular basis of Tousled-Like Kinase 2 activation. Nature Communications, 9(1), 2535. Artikel 2535. https://doi.org/10.1038/s41467-018-04941-y

@article{063a80be3a3d42f785d4b9e68b1426af,

title = "Molecular basis of Tousled-Like Kinase 2 activation",

abstract = "Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.",

author = "Mortuza, {Gulnahar B.} and Dario Hermida and Anna-Kathrine Pedersen and Sandra Segura-Bayona and Blanca L{\'o}pez-M{\'e}ndez and Pilar Redondo and Patrick R{\"u}ther and Irina Pozdnyakova and Garrote, {Ana M} and Mu{\~n}oz, {In{\'e}s G} and Marina Villamor-Pay{\`a} and Cristina Jauset and Olsen, {Jesper V.} and Stracker, {Travis H.} and Guillermo Montoya",

year = "2018",

doi = "10.1038/s41467-018-04941-y",

language = "English",

volume = "9",

pages = "2535",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

number = "1",

}

TY - JOUR

T1 - Molecular basis of Tousled-Like Kinase 2 activation

AU - Mortuza, Gulnahar B.

AU - Hermida, Dario

AU - Pedersen, Anna-Kathrine

AU - Segura-Bayona, Sandra

AU - López-Méndez, Blanca

AU - Redondo, Pilar

AU - Rüther, Patrick

AU - Pozdnyakova, Irina

AU - Garrote, Ana M

AU - Muñoz, Inés G

AU - Villamor-Payà, Marina

AU - Jauset, Cristina

AU - Olsen, Jesper V.

AU - Stracker, Travis H.

AU - Montoya, Guillermo

PY - 2018

Y1 - 2018

N2 - Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.

AB - Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.

U2 - 10.1038/s41467-018-04941-y

DO - 10.1038/s41467-018-04941-y

M3 - Journal article

C2 - 29955062

SN - 2041-1723

VL - 9

SP - 2535

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2535

ER -

Molecular basis of Tousled-Like Kinase 2 activation

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater