Universität zu Köln

Klußmann, Merlin ORCID: 0000-0001-6041-0501, Reuter, Jan, Werner, Christian ORCID: 0000-0001-5263-4994 and Neundorf, Ines ORCID: 0000-0001-6450-3991 (2025). Examining Farnesyltransferase Interaction With Cell‐Permeable CaaX Peptides and the Role of the CaaX Motif in Biological Activity. Journal of Peptide Science, 31 (4). pp. 1-13. Wiley. ISSN 1075-2617

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Abstract

Recently, we presented cell‐permeable CaaX peptides as versatile tools to study intracellular prenylation of proteins. These peptides consist of a cell‐penetrating peptide (CPP) and a C ‐terminal CaaX motif derived from Ras proteins and demonstrated high cellular accumulation and the ability to influence Ras signaling in cancerous cells. Here, we aimed to gain a deeper insight into how such cell‐permeable CaaX peptides, particularly the KRas4B‐derived CaaX‐1 peptide, interact with farnesyltransferase (FTase) and likely influence further intracellular processes. We show that CaaX‐1 is farnesylated by FTase ex cellulo and that an intact CaaX motif is required for modification. A competition experiment revealed a slower farnesylation of CaaX‐1 by FTase compared to a CaaX motif‐containing control peptide. CaaX‐1 inhibited farnesylation of this control peptide at considerably lower concentrations; thus, a higher affinity for FTase is hypothesized. Notably, AlphaFold3 not only predicted interactions between CaaX‐1 and FTase but also suggested interactions between the peptide and geranylgeranyltransferase type I. This finding encourages further investigation, as cross‐prenylation is a well‐known drawback of FTase inhibitors. Our results are further evidence for the usefulness of CaaX peptides as tools to study and manipulate the prenylation of proteins. They offer real potential for the development of novel inhibitors targeting the prenylation pathway.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Klußmann, Merlin UNSPECIFIED https://orcid.org/0000-0001-6041-0501 UNSPECIFIED Reuter, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Christian UNSPECIFIED https://orcid.org/0000-0001-5263-4994 UNSPECIFIED Neundorf, Ines UNSPECIFIED https://orcid.org/0000-0001-6450-3991 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-792193
Identification Number:	10.1002/psc.70009
Journal or Publication Title:	Journal of Peptide Science
Volume:	31
Number:	4
Page Range:	pp. 1-13
Date:	10 March 2025
Publisher:	Wiley
ISSN:	1075-2617
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	Chemistry and allied sciences Life sciences
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79219