Ludwig Eichinger - assoc. RG

Functional analysis of p97/VCP and its interaction partners

The aim of our study is to elucidate the molecular function of p97 in the model organism Dictyostelium discoideum. p97 is evolutionarily highly conserved and it has been shown that p97 missense mutation can cause five human neurodegenerative disorders. We are interested in the functional consequences of selected p97 point mutation, the identification of novel p97 interaction partners and the regulation of p97 functions by individual members of the large family of UBX domain containing proteins.


p97, also known as VCP in Homo sapiens, TER94 in Drosophila melanogaster, CdcD in Dictyostelium discoideum, CDC48 in Saccharomyces cerevisiae, and VAT in Thermoplasma acidophilum, is a ubiquitously expressed, very abundant and highly conserved member of the triple-A (ATPase Associated with diverse cellular Activities) ATPase family. This Mg2+-dependent ATPase 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 nuclear envelope reconstruction, cell cycle, postmitotic Golgi reassembly, suppression of apoptosis, DNA damage response, and endocytosis. In addition, p97 exerts central roles in several protein quality control pathways.

p97 point-mutations can cause neuro-degenerative diseases

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.

p97 has a plethora of interacting proteins

Regulation of p97 functions is mediated by many cofactors. We found that VCP 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 highly conserved WASH (Wiskott Aldrich Syndrome protein and SCAR homolog) complex. The neurobiological 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).

The UBX (ubiquitin regulatory X) domain containing proteins constitute the largest subgroup of p97 interacting proteins. The UBX domain is a conserved 80 amino acids region that shares structural similarity with ubiquitin. One family member is mammalian TUG (Tether containing a UBX domain for GLUT4), which is also known as ASPL (alveolar soft part sarcoma locus) or UBXD9, and involved in insulin stimulated redistribution of the glucose transporter GLUT4 and the assembly of the Golgi complex. We identified an orthologous, uncharacterized Dictyostelium UBX domain containing protein as a novel p97 binding partner, which we accordingly named UBXD9. We assessed functional consequences of human and Dictyostelium p97 mutations on UBXD9 interactions and demonstrated that disease-causing p97 mutations impede the UBXD9-mediated disassembly of human and Dictyostelium p97 hexamers to monomers.


Neurodegenerative diseases are characterized by progressive dysfunction of neurons. Major basic processes include abnormal protein dynamics, protein aggregates and defects in endo- and/or exocytosis due to deficiencies in the endolysosomal system. p97 and associated proteins fulfil critical functions in these processes. Their analysis will lead to a better understanding of the associated disease-related processes.

Selected publications(CMMC-project related)

Clemen, C.S., K. Tangavelou, K-H. Strucksberg, S. Just, L. Gaertner, H. Regus-Leidig, M. Stumpf, J. Reimann, R. Coras, R.O. Morgan, M-P. Fernandez, A. Hofmann, S. Müller, B. Schoser, F-G. Hanisch, W. Rottbauer, I. Blümcke, S. von Hörsten, L. Eichinger, and R. Schröder (2010). Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. Brain 133, 2920-2941.

Arhzaouy, K., K.-H. Strucksberg, S.M. Tung, K. Tangavelou, M. Stumpf, J. Faix, S. Schröder, C.S. Clemen, and L. Eichinger (2012). Heteromeric p97/p97R155C complexes induce dominant negative changes in wild-type and autophagy 9-deficient Dictyostelium strains. PLoS One 7(10), e46879.

Clemen, C.S., L. Eichinger, and R. Schröder (2012). Reply: Hereditary spastic paraplegia caused by a mutation in the VCP gene - VCP: A jack of all trades in neuro- and myodegeneration? Brain 135, 1–3, e224.

Rijal, R., K. Arhzaouy, K-H. Strucksberg, M. Cross, A. Hofmann, R. Schröder, C.S. Clemen*, and L. Eichinger* (2016). Mutant p97 exhibits species-specific changes of its ATPase activity and compromises the UBXD9-mediated monomerisation of p97 hexamers. Eur. J. Cell Biol. 95, 195-207. *Co-senior authors.

Kustermann, M., L. Manta, C. Paone, J. Kustermann, L. Lausser, C. Wiesner, L. Eichinger, C.S. Clemen, R. Schröder, H.A. Kestler, M. Sandri, W. Rottbauer, and S. Just (2018). Loss of the novel Valosin-containing protein (VCP) interactor SWIP interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo. Autophagy, in press.

Song, L., R. Rijal, M. Karow, M. Stumpf, O. Hahn, L. Park, R. Insall, R. Schröder, A. Hofmann, C.S. Clemen, and L. Eichinger (2018). Expression of N471D strumpellin leads to defects in the endolysosomal system. Dis. Model Mech., in revision.

Prof. Dr. Ludwig Eichinger

Center for Biochemistry

Prof. Dr. Ludwig Eichinger
Publications - Ludwig Eichinger

Link to PubMed

Group Members

Sarah Fischer
Malte Karow
Jana Riehl