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Title
Influence of point-mutations within the Stim1 CC1 domain on Homomerisation and Conformational Rearrangements of Stim1 C-terminus / Author Katharina Rothberger
AuthorRothberger, Katharina
CensorRomanin, Christoph
PublishedLinz, 2017
Description62 Blätter : Illustrationen
Institutional NoteUniversität Linz, Masterarbeit, 2017
LanguageEnglish
Document typeMaster Thesis
Keywords (GND)Calciumion / Cytologie / Mutation
URNurn:nbn:at:at-ubl:1-18542 Persistent Identifier (URN)
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 The work is publicly available
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Influence of point-mutations within the Stim1 CC1 domain on Homomerisation and Conformational Rearrangements of Stim1 C-terminus [2.71 mb]
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Abstract (English)

Calcium is one of the major ions responsible for human life. It plays a key role in processes like apoptosis and intracellular messenger processes. For this, the Store Operated Calcium Entry (SOCE) is, as one of the major pathways for Ca2+ signalling, a very important process. It is mediated by Calcium Release Activated Calcium Channels (CRAC), which consists of the stromal interaction molecule (STIM), the calcium sensor unit situated in the ER membrane, and the pore-forming protein Orai in the plasma membrane. Initiated by calcium store depletion, an intermolecular rearrangement of STIMs ER-luminal domain leads to an extended conformation. This active form oligomerises, translocates to the plasma membrane, and activates the pore-forming unit Orai with its C-terminal end. As a result, Orai forms a hexameric pore structure through which calcium can enter the cell. Mutations in both STIM and Orai may lead to dysfunctions in CRAC channel formation, causing severe health problems. One example is the R304W point mutation, located in the cytosolic CC1 domain of STIM1. This gain of function mutation leads to a constitutive active STIM1 protein and therefore constant calcium influx into the cell, which is associated with an autosomal dominant disease called Stormorken syndrome. This rare genetic dysfunction is characterised by a phenotype that includes miosis, muscle fatigue, ichthyosis, and thrombocytopenia. In this thesis, I examine the influence of the R304W mutation on the STIM1 activation process and compare it to the known influence mechanism of L251S using FRET and patch clamp measurements. The results reveal that R304W leads to a constitutive active STIM1 protein due to increased CC11 homomerisation. Furthermore, I demonstrate how the position and polarity of the point mutation affect the constitutive active STIM1.

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