ClpX

Protein Structure

The knowledge of human ClpX protein are majorly based on the investigations on E. Coli protein. The monomer of ClpX protein in E. Coli contains a N-terminal domain and a AAA+ module which consists of a large and a small AAA+ domain.

Complex Assembly

During protease Clp complex assembly, the ClpX subunits form a hexameric ring structure. According to the orientation of ClpX subunits within the ring structure, these subunits can be categorized into two classes: "loadable" subunit (L subunit) and "unloadable" subunit (U subunit). In L subunit, the large and small AAA+ domain form a cleft for nucleotide ATP or ADP binding. However, the large and small AAA+ domains in U subunit rotate ~ 80°, which prevents nucleotide binding. The L and U subunits form a "L-L-U-L-L-U" pattern when they assemble into a hexameric ring, which has the maximum capacity to bind four ATP or ADP. Electro-microscopy (EM) studies showed that ClpX ring structures stack coaxially on either one side or both side of ClpP tetradecamer complex to form ClpXP protease complexes. ATP binding can stabilize the association between ClpX and ClpP ring structures.

Function

ClpX is an ATP-dependent chaperone that can recognize protein substrates by binding to protein degradation tags. These tags can be short unstructured peptide sequences (e.g., ssrA-tag in E coli). As an essential component of ClpP protease complex, ClpX recruits degradable substrates and unfolds their tertiary structure, which requires energy provided by ATP hydrolysis. Subsequently, these ClpX Chaperons transfer protein substrates into the proteolytic chamber formed by ClpP tetradecamer.

Clinical Significance

In mammals, ClpXP protease is a pivotal contributor to mitochondrial protein quality control. A compromised ClpXP function usually leads to the accumulation of damaged proteins and mitochondrial dysfunctions, which believes to be potential causes for neurodegenerative diseases and aging.