Tuesday, December 28, 2010

Proteasomes – The Human Garbage Can

Humans and all eukaryotic organisms (those with nucleated cells) have structures within the cells that are basically recycling bins.  This structure of multiple proteins is called a “Proteasome” and ironically is basically in the shape of a garbage can.  It is composed of a central cylinder shaped core (i.e., 20S, lighter gray sections of model below) created by two rings of a series of b1 to b7 sub-units.  The lid (i.e., 19S cap, dark gray parts of model below) of the proteasome is composed of a series of a1 to a7 sub-units that also creates a channel with a regulatory function.  The top of these a sub-units is composed of Rpt1 and Rpt2 followed by a subunits Rpt3,5,6,7,10, and 12.  The cellular process to degrade waste products starts with a three-step process of labeling them called “ubiquitization”.  The lid collects waste proteins labeled with one or more “ubiquitine” molecules (small black dots in model).  The label(s) are removed and the waste molecule is unfolded as it is fed into the proteasome cylinder.  Several proteolase (enzymatic protein degradation) functions are performed inside the core; b5 for chymotrophic, b2 for typsin-like, and b1 for caspase activities. Once inside the 20S section, b proteases break down the waste protein to simpler components (i.e., peptides).  These are expelled at the bottom cap and are now potentially reusable by the cell.  The net result would be a detoxification of the cell.  The system is named the “Ubiquitine Proteasome System”.  It plays a crucial role ensuring that the interior of whatever type cell it is in does not accumulate waste to levels that become toxic to the cell and interfere with the functions of that cell.

Representation of Yeast Proteasome1

A recent study2 published in 2010 investigated the role this system plays in cardiac muscles.  Dysfunction in the proteasome caused an accumulation of Akt kinase and the transcription factor p53, a mediator of apoptosis (cell self-destruction) resulting in hypertrophic cardiomyopathy and heart failure.  The dysfunction was attributed to the oxidized derivatives identified as Rpt3 and Rpt5, which are part of the lid (19S section).  The oxidative stress of these components was at least partially responsible for the proteasome dysfunction.  The degree of oxidation would adversely affect the proteasome’s ability to deliver the waste proteins to the 20S section.

The proteasome system in skin cells is involved in the clean up of UV damaged tissues and ends up regulating or inhibiting the rate of the repair process.  Similar dysfunctions in the lid section of these proteasomes may be a key to expediting cellular repairs from sun damage.  Skin care product developers may consider additives that would address minimizing this dysfunction and maximize the rate of repair.

The take-home lessons here are, “Make sure you tip your garbage man”.  They serve a very important function.  Also researchers in cellular repair of skin may use this information to discover similar mechanisms in skin metabolism and develop improved sun care products.
Another representation below3

1McDonald,H.B, Byers,B., “A Proteasome Cap Subunit Required for Spindle Pole Body Duplication in Yeast”, Journal of Cell Biology, V.137;539-553;May 5, 1997.

2J.Predmore, S. Powell et. al., “Ubiquitin Proteasome Dysfunction in Human Hypertrophic and Dilated Cardiomyopathies”, The Journal of the American Heart Association,121;997-1004;2010.

3 AngieBioTech.com Image