Abstract:Summary
Jaw1/LRMP is a membrane protein that is localized to the endoplasmic reticulum and outer nuclear membrane. Previously, we revealed that Jaw1 functions to maintain nuclear shape by interacting with microtubules as a Klarsicht/ANC-1/Syne/homology (KASH) protein. The loss of several KASH proteins causes defects in the position and shape of the Golgi apparatus as well as the nucleus, but the effects of Jaw1 depletion on the Golgi apparatus were poorly understood. Here, we found that siRNA-me… Show more
“…As depicted in this review, IRAG1 and IRAG2 are membrane proteins that regulate intracellular Ca 2+ ( Table 1 ) and are substrate proteins of PKGI. IRAG1 is located at the ER [ 2 , 6 ], whereas IRAG2 was not only found at the ER, but also at other cellular localizations, such as the outer nuclear membrane [ 60 ] or the Golgi apparatus [ 81 ]. Hence, it can be speculated whether IRAG1 might be localized at further intracellular positions and if it exerts further, and up to now not established, functions there.…”
Section: Discussionmentioning
confidence: 99%
“…Several components of the LINC-complex are involved in the morphology and position of the Golgi apparatus [ 78 , 79 , 80 ]. As IRAG2 functions as a KASH protein to maintain nuclear shape, it might play a role in the formation of the Golgi apparatus [ 60 , 81 ]. Investigations using B16F10-cells showed that IRAG2 participates in maintaining the Golgi ribbon structure associated with the microtubule network.…”
Section: Functional Features Of Irag2mentioning
confidence: 99%
“…Furthermore, the depletion of IRAG2 disturbs the localization of the Golgi-derived microtubule network, indicating that IRAG2 keeps the compact structure of the microtubule-derived network and is needed to maintain the Golgi morphology. However, the mechanism of how IRAG2 affects the maintenance of the Golgi apparatus still needs to be clarified [ 81 ].…”
The inositol triphosphate-associated proteins IRAG1 and IRAG2 are cGMP kinase substrate proteins that regulate intracellular Ca2+. Previously, IRAG1 was discovered as a 125 kDa membrane protein at the endoplasmic reticulum, which is associated with the intracellular Ca2+ channel IP3R-I and the PKGIβ and inhibits IP3R-I upon PKGIβ-mediated phosphorylation. IRAG2 is a 75 kDa membrane protein homolog of IRAG1 and was recently also determined as a PKGI substrate. Several (patho-)physiological functions of IRAG1 and IRAG2 were meanwhile elucidated in a variety of human and murine tissues, e.g., of IRAG1 in various smooth muscles, heart, platelets, and other blood cells, of IRAG2 in the pancreas, heart, platelets, and taste cells. Hence, lack of IRAG1 or IRAG2 leads to diverse phenotypes in these organs, e.g., smooth muscle and platelet disorders or secretory deficiency, respectively. This review aims to highlight the recent research regarding these two regulatory proteins to envision their molecular and (patho-)physiological tasks and to unravel their functional interplay as possible (patho-)physiological counterparts.
“…As depicted in this review, IRAG1 and IRAG2 are membrane proteins that regulate intracellular Ca 2+ ( Table 1 ) and are substrate proteins of PKGI. IRAG1 is located at the ER [ 2 , 6 ], whereas IRAG2 was not only found at the ER, but also at other cellular localizations, such as the outer nuclear membrane [ 60 ] or the Golgi apparatus [ 81 ]. Hence, it can be speculated whether IRAG1 might be localized at further intracellular positions and if it exerts further, and up to now not established, functions there.…”
Section: Discussionmentioning
confidence: 99%
“…Several components of the LINC-complex are involved in the morphology and position of the Golgi apparatus [ 78 , 79 , 80 ]. As IRAG2 functions as a KASH protein to maintain nuclear shape, it might play a role in the formation of the Golgi apparatus [ 60 , 81 ]. Investigations using B16F10-cells showed that IRAG2 participates in maintaining the Golgi ribbon structure associated with the microtubule network.…”
Section: Functional Features Of Irag2mentioning
confidence: 99%
“…Furthermore, the depletion of IRAG2 disturbs the localization of the Golgi-derived microtubule network, indicating that IRAG2 keeps the compact structure of the microtubule-derived network and is needed to maintain the Golgi morphology. However, the mechanism of how IRAG2 affects the maintenance of the Golgi apparatus still needs to be clarified [ 81 ].…”
The inositol triphosphate-associated proteins IRAG1 and IRAG2 are cGMP kinase substrate proteins that regulate intracellular Ca2+. Previously, IRAG1 was discovered as a 125 kDa membrane protein at the endoplasmic reticulum, which is associated with the intracellular Ca2+ channel IP3R-I and the PKGIβ and inhibits IP3R-I upon PKGIβ-mediated phosphorylation. IRAG2 is a 75 kDa membrane protein homolog of IRAG1 and was recently also determined as a PKGI substrate. Several (patho-)physiological functions of IRAG1 and IRAG2 were meanwhile elucidated in a variety of human and murine tissues, e.g., of IRAG1 in various smooth muscles, heart, platelets, and other blood cells, of IRAG2 in the pancreas, heart, platelets, and taste cells. Hence, lack of IRAG1 or IRAG2 leads to diverse phenotypes in these organs, e.g., smooth muscle and platelet disorders or secretory deficiency, respectively. This review aims to highlight the recent research regarding these two regulatory proteins to envision their molecular and (patho-)physiological tasks and to unravel their functional interplay as possible (patho-)physiological counterparts.
“…JAW1/LRMP (lymphoid restricted membrane protein) is an atypical KASH protein that is localised in the endoplasmic reticulum and outer nuclear membrane, and is specifically expressed in certain cells of the immune system, small intestine, pancreas and taste buds 31 – 33 . It interacts with SUN1 and microtubules, and is required to maintain nuclear shape and Golgi structure 31 , 32 . Fig.…”
The LINC complex transmits cytoskeletal forces into the nucleus to control the structure and movement of nuclear contents. It is formed of nuclear SUN and cytoplasmic KASH proteins, which interact within the nuclear lumen, immediately below the outer nuclear membrane. However, the symmetrical location of KASH molecules within SUN-KASH complexes in previous crystal structures has been difficult to reconcile with the steric requirements for insertion of their immediately upstream transmembrane helices into the outer nuclear membrane. Here, we report the crystal structure of the SUN-KASH complex between SUN1 and JAW1/LRMP (KASH6) in an asymmetric 9:6 configuration. This intertwined assembly involves two distinct KASH conformations such that all six KASH molecules emerge on the same molecular surface. Hence, they are ideally positioned for insertion of upstream sequences into the outer nuclear membrane. Thus, we report a SUN-KASH complex architecture that appears to be directly compatible with its biological role.
“…KASH5 is a meiosis-specific coiled-coil protein that functions as a dynein activating adapter that transmits microtubule forces to meiotic chromosome and is essential for their synapsis and fertility ( Horn et al, 2013b ; Agrawal et al, 2022 ; Garner et al, 2022 ). The final KASH protein, JAW1/LRMP/IRAG2, interacts with microtubules, and is required to maintain nuclear shape and Golgi structure ( Kozono et al, 2018 ; Okumura et al, 2023 ). Hence, the combination of five SUN proteins (and their multiple isoforms) and six KASH proteins achieve the widespread, varied and essential functions of the LINC complex in mammals.…”
The LINC complex, consisting of interacting SUN and KASH proteins, mechanically couples nuclear contents to the cytoskeleton. In meiosis, the LINC complex transmits microtubule-generated forces to chromosome ends, driving the rapid chromosome movements that are necessary for synapsis and crossing over. In somatic cells, it defines nuclear shape and positioning, and has a number of specialised roles, including hearing. Here, we report the X-ray crystal structure of a coiled-coiled domain of SUN1’s luminal region, providing an architectural foundation for how SUN1 traverses the nuclear lumen, from the inner nuclear membrane to its interaction with KASH proteins at the outer nuclear membrane. In combination with light and X-ray scattering, molecular dynamics and structure-directed modelling, we present a model of SUN1’s entire luminal region. This model highlights inherent flexibility between structured domains, and raises the possibility that domain-swap interactions may establish a LINC complex network for the coordinated transmission of cytoskeletal forces.
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