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Cross-talk unfolded: MARCKS proteins
Anna Arbuzova1, Arndt A P Schmitz, Guy Vergères
1Department of Physiology and Biophysics, Health Sciences Center, State University of New York, Stony Brook, NY 11794-8661, U.S.A.
Abstract:
The proteins of the MARCKS (myristoylated alanine-rich C kinase substrate) family were first identified as prominent substrates of protein kinase C (PKC). Since then, these proteins have been implicated in the regulation of brain development and postnatal survival, cellular migration and adhesion, as well as endo-, exo- and phago-cytosis, and neurosecretion. The effector domain of MARCKS proteins is phosphorylated by PKC, binds to calmodulin and contributes to membrane binding. This multitude of mutually exclusive interactions allows cross-talk between the signal transduction pathways involving PKC and calmodulin. This review focuses on recent, mostly biophysical and biochemical results renewing interest in this protein family. MARCKS membrane binding is now understood at the molecular level. From a structural point of view, there is a consensus emerging that MARCKS proteins are "natively unfolded". Interestingly, domains similar to the effector domain have been discovered in other proteins. Furthermore, since the effector domain enhances the polymerization of actin in vitro, MARCKS proteins have been proposed to mediate regulation of the actin cytoskeleton. However, the recent observations that MARCKS might serve to sequester phosphatidylinositol 4,5-bisphosphate in the plasma membrane of unstimulated cells suggest an alternative model for the control of the actin cytoskeleton. While myristoylation is classically considered to be a co-translational, irreversible event, new reports on MARCKS proteins suggest a more dynamic picture of this protein modification. Finally, studies with mice lacking MARCKS proteins have investigated the functions of these proteins during embryonic development in the intact organism.
Insights
Myristoylated alanine-rich C kinase substrate (MARCKS) proteins are crucial for cell functions, with new research revealing their molecular-level membrane binding and dynamic myristoylation. These findings offer insights into cellular signaling and actin cytoskeleton regulation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- MARCKS proteins are key substrates of protein kinase C (PKC).
- They regulate diverse cellular processes including brain development, migration, and membrane trafficking.
- MARCKS effector domain interacts with calmodulin and membranes, mediating signal transduction cross-talk.
Purpose of the Study:
- To review recent biophysical and biochemical findings on MARCKS protein family.
- To elucidate the molecular mechanisms of MARCKS membrane binding and structural properties.
- To explore the proposed roles of MARCKS in actin cytoskeleton regulation and phosphatidylinositol 4,5-bisphosphate sequestration.
Main Methods:
- Biophysical and biochemical analyses.
- Structural studies.
- Studies on MARCKS-deficient mice.
Main Results:
- MARCKS membrane binding is understood at the molecular level.
- MARCKS proteins are characterized as natively unfolded.
- Evidence suggests MARCKS proteins sequester phosphatidylinositol 4,5-bisphosphate and dynamically regulate myristoylation.
Conclusions:
- Recent findings provide a molecular understanding of MARCKS protein interactions and functions.
- MARCKS proteins play a significant role in regulating the actin cytoskeleton.
- Myristoylation of MARCKS proteins is more dynamic than previously thought.