Structural studies of fertilisation and zona pellucida module proteins - Luca Jovine
From microscopic algae to gigantic blue whales, the beginning of every sexually reproducing organism on the planet is marked by the encounter between female and male gametes, egg and sperm, at fertilisation. Due to its fundamental role in ensuring the transmission of genetic information between generations, this crucial event has become a true icon of biology that has captivated mankind for centuries. But how does this process actually take place at the molecular level?
By harnessing the power of structural biology, our laboratory has started to shed light on the molecular recognition events that underlie the origin of a new life.
The first interaction between gametes happens when sperm contacts the surface of the egg coat, called zona pellucida (ZP) in mammals and vitelline envelope (VE) in non-mammals. This is followed by a second recognition event that triggers fusion of the gametes after sperm has penetrated the VE/ZP and contacted the plasma membrane of the oocyte.
By determining 3D structures of ZP2 and ZP3 (major egg coat components that have long been implicated in sperm binding) as well as structurally characterising Juno and Izumo (counterpart proteins on egg and sperm whose interaction is required for gamete fusion), our group has yielded the first atomic-resolution information on molecules essential for both steps of fertilisation in mammals. By also solving structures of mollusc sperm receptor VERL in complex with its binding partner on sperm, protein lysin (figure), we provided a first example of how gametes contact each other at the very beginning of fertilisation and revealed that - despite being separated by 600 million years of evolution - invertebrate and vertebrate egg coat proteins use the same basic molecular architecture to interact with sperm.
In parallel with these studies, our group is also investigating a family of biomedically important human proteins – such as urinary Tamm-Horsfall protein/uromodulin (UMOD) and endothelial glycoprotein endoglin (ENG)/CD105 – that are similar in structure to fertilisation molecules but which perform completely different functions in the body. While our work on fertilisation proteins has important implications for both understanding human infertility and informing the future development of targeted non-hormonal contraceptives, X-ray crystallographic and cryo-EM studies on UMOD, ENG and related proteins allowed us to interpret a large number of human mutations linked to severe pathologies, such as urinary and vascular diseases, non-syndromic deafness and cancer. At the same time, our studies of UMOD and structurally similar human glycoprotein GP2 recently revealed how these molecules counteract bacterial infections in the urinary tract and gastrointestinal system, respectively.
Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH.
Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L
Nat Struct Mol Biol 2022 Mar;29(3):190-193
Cryo-EM structure of native human uromodulin, a zona pellucida module polymer.
Stsiapanava A, Xu C, Brunati M, Zamora-Caballero S, Schaeffer C, Bokhove M, et al
EMBO J 2020 39:e106807
Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility.
Nishimura K, Dioguardi E, Nishio S, Villa A, Han L, Matsuda T, et al
Nat Commun 2019 07;10(1):3086
Structure of Zona Pellucida Module Proteins.
Bokhove M, Jovine L
Curr. Top. Dev. Biol. 2018 ;130:413-442
Structural Basis of Egg Coat-Sperm Recognition at Fertilization.
Raj I, Sadat Al Hosseini H, Dioguardi E, Nishimura K, Han L, Villa A, et al
Cell 2017 Jun;169(7):1315-1326.e17
Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1.
Saito T, Bokhove M, Croci R, Zamora-Caballero S, Han L, Letarte M, et al
Cell Rep 2017 05;19(9):1917-1928
The structure of sperm Izumo1 reveals unexpected similarities with Plasmodium invasion proteins.
Nishimura K, Han L, Bianchi E, Wright GJ, de Sanctis D, Jovine L
Curr. Biol. 2016 07;26(14):R661-2
Divergent evolution of vitamin B9 binding underlies Juno-mediated adhesion of mammalian gametes.
Han L, Nishimura K, Sadat Al Hosseini H, Bianchi E, Wright GJ, Jovine L
Curr. Biol. 2016 Feb;26(3):R100-1
A structured interdomain linker directs self-polymerization of human uromodulin.
Bokhove M, Nishimura K, Brunati M, Han L, de Sanctis D, Rampoldi L, et al
Proc. Natl. Acad. Sci. U.S.A. 2016 Feb;113(6):1552-7
Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation.
Cherry AL, Finta C, Karlström M, Jin Q, Schwend T, Astorga-Wells J, et al
Acta Crystallogr. D Biol. Crystallogr. 2013 Dec;69(Pt 12):2563-79
Insights into egg coat assembly and egg-sperm interaction from the X-ray structure of full-length ZP3.
Han L, Monné M, Okumura H, Schwend T, Cherry AL, Flot D, et al
Cell 2010 Oct;143(3):404-15
Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats.
Monné M, Han L, Schwend T, Burendahl S, Jovine L
Nature 2008 Dec;456(7222):653-7
- Nobel Assembly at Karolinska Institutet Membership (2019-)
- EMBO Membership (2018-)
- Hugo Theorell Prize for Biophysics (2013)
- Göran Gustafsson Prize for Chemistry (2012)
- Erik K. Fernström Prize (2011)
- Sven och Ebba-Christina Hagberg Prize for Medical Research (2011)