The cells of higher life forms, so-called eukaryotic cells, are subdivided through many internal membranes made of lipid bilayers. The internal membranes assume numerous shapes, like spheres, tubes or parallel sheets. Outside of cells, biological membranes adopt usually flat shapes and the question arises, how do eukaryotic cells sculpt their inner membranes? The question of flat membrane sculpting is particularly interesting also as mature cells constantly produce new membrane shapes, for example spherical vesicles filled with certain biomolecules destined for release into the extracellular space, a process called exocytosis. The cell has many mechanisms available for sculpting its membranes, one of them relying on proteins called BAR domains that act from the surface of lipid bilayers. Molecular modeling with NAMD and VMD has provided valuable views of BAR domains at work in case of the so-called N-BAR family (see the earlier highlights Protein Teamwork, Jun 2009 and Proteins Sculpting Cell Interior, Sep 2008). Researchers report now an extension of the earlier studies to the F-BAR domain family of membrane sculpting proteins. The new modeling work is particularly exciting as it can be directly compared to electron microscopy images of membrane tubes sculpted from flat membranes in experiments done outside of cells. The new studies reveal how F-BAR domains sculpt tubular membranes through the shape of dimerized domains and through F-BAR domains not acting individually, but as an army of F-BAR domains adopting an ordered formation on one side of the membrane. More on our F-BAR domain web page.
The Golgi apparatus found in so-called eukaryotic cells acts like Amazon.com, namely accepting delivery of newly synthesized proteins, packaging them, and sending them out.
However, in comparison to Amazon.com the Golgi apparatus uses immensely more advanced packaging materials made of a multitude of lipids.
The various lipids form membranes in the shape of vesicles.
Depending on lipid type specific goods are packaged inside the vesicles, specific
locations in the cell receive the packages, content is emptied there and packages are retrieved.
To achieve the series of steps just outlined, lipids as the main actors need to be coordinated.
One way is to recognize lipids forming vesicle membranes and to modify them to be readied for a subsequent step, for example going from release step to retrieval step.
For this purpose eukaryotic cells engage a special class of proteins,
named kinases, that can recognize membrane lipids and phosphorylate them, adding a so-called phosphate group.
As reported recently,
a team of experimental and computational scientists determined the atomic structure of a key member in the kinase family,
phosphatidylinositol 4-kinase (PI4K).
The scientists discovered not only the structure, but also how PI4K captures and phosphorylates a particular type of lipid molecule,
thereby changing a vesicular membrane and turning on the next step in the cellular package delivery system.
The discoveries, made possible through the software
NAMD and VMD,
are expected to have an impact on the design of novel drugs that suppress cancer cell growth. More on our kinase website.
For centuries, millions of people around the globe have been troubled with a movement disorder that usually starts with a tremor in one hand. The disorder, later known as Parkinson's disease, affects commonly older individuals and disrupts patient's movement, sleep and speech from the brain. There is currently no cure for the disease. Key to the disease, progressively occurring in patient's brain, is the loss of neuron cells due to aggregation of a small protein named α-synuclein. Extensive studies have been carried out, yet the function of the protein remains a mystery. It is amazing that aggregation of such small proteins eventually leads to neuronal cell death and generates tremendous difficulties in peoples' life.
In a recent report, a team of computational scientists attributed the cause of α-synuclein aggregation to a hairpin structure involving just a small region (amino acids 38-53) in the middle of the protein. With extensive simulations (over 180 μs in total), the researchers revealed that a short fragment encompassing region 38-53, exhibiting a high probability of forming a β-hairpin structure, is a key region during α-synuclein aggregation. Moreover, the researchers predicted a mutation that impedes β-hairpin formation, thereby retarding α-synuclein aggregation. The discoveries, made possible through the software
NAMD and VMD, are expected to shed light on the mechanism underlying Parkinson's disease and to inspire the design of drugs. More on our α-synuclein website.