Poster Presentation The 45th Lorne Conference on Protein Structure and Function 2020

Two-component pore formation by the CDCL proteins ALY short and ALY long from Elizabethkingia anophelis (#104)

Bronte A Johnstone 1 , Sara L Lawrence 2 , Michelle P Christie 1 , Rodney K Tweten 3 , Craig J Morton 1 , Michael W Parker 1 2
  1. Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
  2. ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  3. Department of Microbiology and Immunology, University of Oklahoma, Oklahoma City, OK 73104, USA

Cholesterol-dependent cytolysins (CDCs) are bacterial pore-forming toxins that are secreted as soluble monomers and oligomerise into large circular pre-pores on the surface of cholesterol-rich membranes. Various structural transitions results in insertion of β-hairpins into the lipid bilayer, forming a large β-barrel pore that results in cell lysis (1). A highly conserved structural motif of CDCs was subject to in silico analysis, yielding more than 180 putative genes containing the motif. The protein products of these genes are designated the name “CDC-like” (CDCL) proteins and derive from predominantly Gram-negative bacterial phyla. Many of these CDLS exist as homologous pairs. One partner of the CDCL pair, termed CDCL long, consists of four domains: three similar to CDCs and a unique fourth domain. The other partner, CDCL short, possesses three domains, all similar to CDCs. One CDCL pair, referred to as ALY long (ALYL) and ALY short (ALYS) originate from the species Elizabethkingia anophelis. We have solved the crystal structure of ALYL, which consists of characteristic CDC domain 1 – 3 structure; however, domain 4 differs from that of CDCs significantly. In the presence of lipids, ALYforms a pore-like oligomer, as visualised by negative-staining TEM. Furthermore, in the presence of lipids, ALYin combination with ALYforms a pore structure of the same diameter but with slight visual differences than ALYalone. Unlike CDCs, formation of these pores is not cholesterol dependent. To determine the atomic structure of both pores, cryo-EM single-particle analysis is currently being pursued. Oligomers of an ALYand ALYcomplex are also formed in the absence of lipids, although these oligomers are arc-like structures, indicating incomplete formation of the pore. Investigation of binding events between ALYand ALYL, in addition to lipid specificity and factors that influence pore formation, are ongoing.

  1. Christie MP, Johnstone BA, Tweten RK, Parker MW, Morton CJ (2018) “Cholesterol-dependent cytolysins: from water-soluble state to membrane pore”, Biophys Rev. 10(5), 1337–1348.