Ludwig Eichinger - assoc. RG

Analysis of the function of p97/VCP in Dictyostelium discoideum

Abstract

p97, also known as VCP in Homo sapiens, is a ubiquitously expressed, very abundant and evolutionarily highly conserved member of the triple-A (ATPase Associated with diverse cellular Activities) ATPase family. The protein has a tripartite structure comprising an N-terminal CDC48 domain followed by the D1 and D2 domains that bind and hydrolyse ATP. p97 assembles into a ring shaped hexameric complex of six identical subunits where the D domains form the central cylinder surrounded by the CDC48 domains. p97 is involved in a plethora of cellular processes such as postmitotic nuclear envelope and Golgi reconstruction, suppression of apoptosis, DNA damage response, and endocytosis. In addition, p97 exerts central roles in several protein quality control pathways.
To date, more than forty heterozygous disease-causing missense mutations have been described in human p97. Initially, it was shown that p97 point mutations cause the late-onset and slowly progressive multi-system disorder IBMPFD (Inclusion Body Myopathy associated with Paget disease of bone and Fronto-temporal Dementia). Meanwhile, four more neurodegenerative disorders, ALS (Amyotropic Lateral Sclerosis), Parkinson’s disease, HSP (Hereditary Spastic Paraplegia) and CMT2A2 (Charcot-Marie-Tooth disease type 2) have been attributed to p97 missense mutations. The exact molecular mechanisms by which p97 mutations cause these late-onset disorders remain elusive. However, an increasing number of reports showed mutation-specific effects on p97 interaction partners with functional consequences on endosomal trafficking, endoplasmic reticulum associated degradation (ERAD) of proteins, autophagosome maturation, ATPase activity or 20S proteasome binding. We study the function of wild-type and point-mutated p97 in D. discoideum, investigate its interactions with strumpellin and other known binding partners and want to transfer newly acquired knowledge in D. discoideum to the human system. An additional goal of our work is the identification of novel and conserved p97 binding partners, a task for which D. discoideum is perfectly suited.

Clinical/medical relevance and sustainability in disease understanding

p97 directly interacts with strumpellin (KIAA0196), which in its mutant form causes a severe and relatively pure motor form of adult-onset HSP (SPG8, OMIM #603563). Furthermore, strumpellin has been identified as a component of the evolutionarily highly conserved WASH (Wiskott Aldrich Syndrome protein and SCAR homolog) complex. The neurobio-logical relevance of this protein complex is highlighted by the observation that mutations in the WASH complex subunit SWIP (Strumpellin and WASH Interacting Protein) have been attributed to cause familial autosomal recessive intellectual disability (ARID).


Prof. Dr. rer. nat. Ludwig Eichinger

Institute for Biochemistry I

Prof. Dr. rer. nat. Ludwig Eichinger
Publications - Ludwig Eichinger

Link to PubMed