Type I Protein Secretion—Deceptively Simple yet with a Wide Range of Mechanistic Variability across the Family

Abstract

A very large type I polypeptide begins to reel out from a ribosome; minutes later, the still unidentifiable polypeptide, largely lacking secondary structure, is now in some cases a thousand or more residues longer. Synthesis of the final hundred C-terminal residues commences. This includes the identity code, the secretion signal within the last 50 amino acids, designed to dock with a waiting ATP binding cassette (ABC) transporter. What happens next is the subject of this review, with the main, but not the only focus on hemolysin HlyA, an RTX protein toxin secreted by the type I system. Transport substrates range from small peptides to giant proteins produced by many pathogens. These molecules, without detectable cellular chaperones, overcome enormous barriers, crossing two membranes before final folding on the cell surface, involving a unique autocatalytic process.Unfolded HlyA is extruded posttranslationally, C-terminal first. The transenvelope "tunnel" is formed by HlyB (ABC transporter), HlyD (membrane fusion protein) straddling the inner membrane and periplasm and TolC (outer membrane). We present a new evaluation of the C-terminal secretion code, and the structure function of HlyD and HlyB at the heart of this nanomachine. Surprisingly, key details of the secretion mechanism are remarkably variable in the many type I secretion system subtypes. These include alternative folding processes, an apparently distinctive secretion code for each type I subfamily, and alternative forms of the ABC transporter; most remarkably, the ABC protein probably transports peptides or polypeptides by quite different mechanisms. Finally, we suggest a putative structure for the Hly-translocon, HlyB, the multijointed HlyD, and the TolC exit.

Structure–Function Relationships Underlying the Capacity of Bordetella Adenylate Cyclase Toxin to Disarm Host Phagocytes

“…The Hly moiety of CyaA harbors within the last 74 residues an unprocessed secretion signal that is recognized by the T1SS apparatus formed by the CyaBDE proteins across the bacterial cell wall [ 16 , 92 ]. Led by the C-terminal sequence, the toxin is extruded through the T1SS conduit in an unfolded state, directly from the calcium-depleted bacterial cytosol into the host body fluids containing millimolar concentrations of free calcium ions [ 9 , 15 , 93 , 94 ]. At the low concentrations of calcium ions inside the bacterial cytosol, the RTX domain remains intrinsically disordered and highly hydrated [ 75 , 95 , 96 , 97 ].…”

Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics

“…Bioinformatics analysis reveals a uniquely organized cluster in the genome of the Gram-negative bacterium Hyalangium minutum DSM 14724 that may determine the production of two putative McC-like compounds. The cluster contains two genes coding for putative precursor peptides, MccA 1 and MccA 2 , two mccB genes, encoding THIF-like adenylyl transferases, and three genes whose products likely constitute a complex ABC-type transporter with integrated HlyD-like translocator and C39-like peptidase (18) (Fig. 2A).…”

Glycoside Hydrolase Genes Are Required for Virulence of Agrobacterium tumefaciens on Bryophyllum daigremontiana and Tomato

“…One gene (melA) is located next to a gene (Atu4666) whose protein product has homology to HlyD, a membrane-fusion protein of the type 1 secretion system (T1SS) (Fig. 2), and thus MelA may be secreted using this system (28). All seven proteins lack the basic region identified as involved in protein secretion via the T4SS (1).…”