Multiscale Computational Dissection of CCRL2-Mediated Chemerin Presentation

Journal of Chemical Information and Modeling, vol. 65, pp. 13400–13419

Abstract

Chemokine-like receptor CCRL2 is a nonsignaling atypical GPCR that presents chemerin to its cognate receptor CMKLR1 (ChemerinR1), a process essential for the recruitment of inflammatory cells. Despite their biological importance, the structural determinants of CCRL2-chemerin recognition remain poorly defined. Here, we present a comprehensive multiscale computational study that integrates coarse-grained and all-atom molecular dynamics simulations with structural modeling to investigate CCRL2-chemerin interaction. Our results reveal a flexible yet stable binding interface primarily mediated by chemerin's β1 strand and CCRL2's extracellular loop 2, while the C-terminal region of chemerin remains accessible for CMKLR1 engagement. Electrostatic interactions between CCRL2 N-terminus and chemerin's loop 3 further stabilize the complex without triggering intracellular signaling. A modeled ternary CCRL2-chemerin-CMKLR1 complex provides a putative mechanistic framework in which CCRL2 aligns chemerin to promote efficient CMKLR1 activation. Mapping of naturally occurring missense variants onto this interface suggests that sequence variation at specific residues may influence receptor-ligand stability and function. Together, these findings suggest a structural basis of CCRL2-mediated chemerin presentation and may help improve our understanding of its role in immune signaling.

Authors 12

1. Samuele Di Cristofano

   Istituto Pasteur · Sapienza University of Rome

   Affiliation as printed

   Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy

2. Klevia Dishnica

   University of Verona · University of Stavanger

   Affiliation as printed

   Department of Biotechnology, University of Verona, Strada le Grazie 15, Verona 37134, Italy

   Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, Kristine Bonnevies vei 22, Stavanger 4021, Norway

3. Alessandro Marchetto Aachen Department of Biology Faculty of Mathematics, Computer Science and Natural Sciences

   Forschungszentrum Jülich · RWTH Aachen University

   Affiliation as printed

   Computational Biomedicine, Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich 52428, Germany

   Department of Biology, Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University, Templergraben 59, Aachen D-52062, Germany

4. Rui Pedro Ribeiro

   University of Verona

   Affiliation as printed

   Department of Biotechnology, University of Verona, Strada le Grazie 15, Verona 37134, Italy

5. Mattia Laffranchi

   Istituto Pasteur · Sapienza University of Rome

   Affiliation as printed

   Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy

6. Elena Cerioni

   Istituto Pasteur · Sapienza University of Rome

   Affiliation as printed

   Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy

7. Francesco Quilli

   Istituto Pasteur · Sapienza University of Rome

   Affiliation as printed

   Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy

8. Eleonora Bonanni

   Istituto Pasteur · Sapienza University of Rome

   Affiliation as printed

   Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy

9. Alejandro Giorgetti

   University of Verona

   Affiliation as printed

   Department of Biotechnology, University of Verona, Strada le Grazie 15, Verona 37134, Italy

10. Giulia Rossetti Aachen Department of Neurology

    Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Supercomputing Centre · RWTH Aachen University

    Affiliation as printed

    Computational Biomedicine, Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich 52428, Germany

    Department of Neurology, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, Aachen 52074, Germany

    Jülich Supercomputing Center, Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich 52428, Germany

11. Tiziana Borsello

    University of Milan · Mario Negri Institute for Pharmacological Research

    Affiliation as printed

    Department of Neuroscience, Mario Negri Institute of Pharmacological Research IRCCS, Via Mario Negri 2, Milan 20156, Italy

    Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy

12. Domenico Raimondo corresponding

    Istituto Pasteur · Sapienza University of Rome

    Affiliation as printed

    Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome 00161, Italy