title: A conditional gating mechanism assures the integrity of the molecular force-sensor titin kinase.
abstract: As more and more recent investigations point out, force plays an important role in cellular regulation mechanisms. Biological responses to mechanical stress are often based on force-induced conformational changes of single molecules. The force sensor, titin kinase, is involved in a signaling complex that regulates protein turnover and transcriptional adaptation in striated muscle. The structural architecture of such a force sensor determines its response to force and must assure both activity and mechanical integrity, which are prerequisites for its function. Here, we use single-molecule force-clamp spectroscopy to show that titin kinase is organized in such a way that the regulatory domains have to unfold before secondary structure elements that determine the overall fold and catalytic function. The stepwise unfolding over many barriers with a topologically determined sequence assures that the protein can react to force by conformational changes while maintaining its structural integrity.
authors: Center for NanoScience, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: Stefan W
authors: SW
authors: Stahl
authors: Elias M
authors: EM
authors: Puchner
authors: Alexander
authors: A
authors: Alexandrovich
authors: Mathias
authors: M
authors: Gautel
authors: Hermann E
authors: HE
authors: Gaub
mesh_terms: D055162:Biocatalysis; D001696:Biomechanical Phenomena; D064211:Connectin; D003599:Cytoskeleton / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry; D006801:Humans; D008390:Markov Chains; D055595:Mechanical Phenomena; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding
chemical_list: D064211:Connectin; D005353:Fibronectins; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases