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Mechanisms of STIM1-mediated endoplasmic reticulum-plasma membrane (ER-PM) contact formation

Chung, Shan-Hua

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The coupling of endoplasmic reticulum (ER) and plasma membrane (PM) is crucial for calcium (Ca2+) homeostasis. STIM1 and STIM2 are type I membrane proteins of the ER and function as Ca2+ sensors in a process known as store-operated calcium entry (SOCE). They sense a drop in luminal Ca2+ concentration and undergo conformational changes and oligomerization. The active oligomerized STIM proteins translocate to ER-PM contact sites, where they bind to phosphoinositides (PIPs) at the inner leaflet of the PM via their lysine (K)- rich domains and activate Orai1, a pore-forming Ca2+ release-activated Ca2+ (CRAC) channel subunit in the PM. I found that STIM2, but not STIM1, contains a di-lysine ER-retention signal. This signal restricts the function of STIM2 as Ca2+ sensor to the ER while STIM1 can reach the PM via the classical secretary pathway. The intracellular distribution of STIM1 is regulated in a cell-cycle-dependent manner with cell surface expression of STIM1 during mitosis. Efficient retention of STIM1 in the ER during interphase depends on its K-rich domain and a di-arginine ER retention signal. SOCE enhances ER retention, suggesting that trafficking of STIM1 is regulated and this regulation contributes to STIM1’s role as multifunctional component in Ca2+-signaling. In contrast to mitotic cells, interphase cells retain most of their STIM1 intracellularly. Under resting condition, the ER-resident STIMs are preferentially located in PI(4,5)P2 containing preexisting ER-PM contact sites, which are expanded upon ER Ca2+ depletion. The lipid-binding, K-rich domains are required to localize STIM proteins in preexisting ERPM contact sites. Moreover, STIM2 recruits ER more efficiently to the PM. This is consistent with the fact that STIM2 has higher lipid-binding affinity and lower activation threshold than STIM1 and that STIM2 functions as a regulator of basal Ca2+ homeostasis. Finally, I studied the role of microtubules in ER-PM contact site formation. I observed that STIM1 aligns along microtubules. Alignment of STIM proteins with microtubules is a conserved process. In addition to accumulation of STIM1 at microtubule plus ends, STIM1 moves along microtubules in an EB-1-independent manner. I identified two EB-1- independent microtubule-binding sites located within the C-terminus of STIM1 and found that oligomerization increases the EB-1-independent microtubule-binding affinity of STIM1. However, the physiological function of this EB1-independent microtubule binding activity remains elusive.

Item Type: Dissertation
Supervisor: Seedorf, PD Dr. Matthias
Place of Publication: Heidelberg
Date of thesis defense: 25 September 2014
Date Deposited: 21 Oct 2014 13:35
Date: 2014
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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