Protein Name

Salmonella effector protein SopA


Salmonella bacterium

Biological Context

Ubiquitin(Ub) is a small protein with 76 amino acids expressed in all eukaryotes. The amino acid sequences are almost identical in all eukaryotes. This indicates that ubiquitin has universal functions in eukaryotic cellular processes. The attachment of ubiquitin to proteins regulates a broad range of cellular reactions, including cell-cycle progression, immune responses, DNA repair and transcription. The most prominent being is protein degradation reaction termed ubiquitin-proteasome system (Fig.1). Unnecessary proteins are ubiquitinated through three enzymes E1, E2 and E3, and degraded by proteasomes. Most E3s belong to either the RING-domain or HECT-domain families of proteins.

Salmonella enterica serovar typhimurium has evolved to coexist with its eukaryotic hosts. The bacterium delivers a variety of effector proteins into the host cell to promote bacterial entry and survival. Although the detailed mechanisms remain largely unknown, studies have indicated that a likely strategy is to exploit host cellular pathways through functional mimicry. SopA, a Salmonella effector protein, mimics the eukaryotic HECT E3. To understand the molecular basis of how bacterial SopA mimics eukaryotic HECT E3, the crystal structure of Salmonella SopA was determined.

(Fig.1) Ubiquitin-proteasome system

Ubiquitins are attached to substrate proteins through an enzyme cascade consisting of E1, E2 and E3 enzymes.
step 1: E1 activates the C terminus of ubiquitin by forming a thioester bond with the terminal carboxyl group of ubiquitin.
step 2: The activated ubiquitin is transferred from E1 to the active site cysteine of an E2 enzyme, preserving the thioester linkage.
step 3: E3 interact with both the substrates and E2, facilitating transfer of ubiquitin to lysine residues of substrate proteins.
Ubiqutins are attached to substrate continuously by repeating this three processes.
26s proteasome degrades the substrate with recognizing attached ubiquitins.

Structure Description


The crystal structure of SopA consists of three structural domains: an N-terminal b-helix, a central elongated region and a C-terminal globular domain (Fig.2). Although SopA shares little sequence similarity with eukaryotic HECT E3s, the overall architecture resembles HECT E3. For example, E6AP (human HECT E3) has a bilobal archtecture consisting of two domain: N lobe and C lobe. (Fig.3). The central and C-terminal domain of SopA are reminiscent of this archtecture. The conformational flexibility of the C-lobe relative to the N-lobe is essential for catalyzing substrate ubiquitination in HECT E3. SopA also exhibits this flexibility (Fig.4).

2 3
(Fig.2) Structure of SopA (Fig.3) Structure of E6AP
(Fig.4) Flexibility of C-lobe

In addition, the active site loop (residues: 747-755) was located on the surface of the molecule facing the b-helix domain. This configuration also corresponds with HECT E3. The residues surrouding the loop are very important to the function. It was shown in both SopA and HECT E3s that the mutation of these residues reduces the ubiquination activity substantially. These results indicate that SopA is a unique HECT E3 evolved from the coevolutionary selective pressure at the bacterium-host interface.%

(*)Since the substrate and E2 binding site remain unclear in SopA and HECT E3s, they are not comparable.

Protein Data Bank (PDB)



Diao, J. Zhang, Y. Huibregtse, J.M. Zhou, D. Chen, J.; "Crystal structure of SopA, a Salmonella effector protein mimicking a eukaryotic ubiquitin ligase."; Nat.Struct.Mol.Biol.; (2008) 15:65-70 PubMed:18066077.


author: Jun-ichi Ito

Japanese version:PDB:2QYU