Abstract
Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly up-regulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases. It shares sequence homology with three enzymes (STEAP2–STEAP4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ∼3.0-Å cryo-EM structure of trimeric human STEAP1 bound to three antigen-binding fragments (Fabs) of the clinically used antibody mAb120.545. The structure revealed that STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells revealed that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, suggesting that STEAP1 functions as a ferric reductase in STEAP heterotrimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and may be useful in the design of new therapeutic strategies to target STEAP1 in cancer.
Highlights
Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly upregulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases
Since its discovery in 1999 as a multispan membrane protein highly expressed on prostate cancer cells [1], six-transmembrane epithelial antigen of the prostate 1 (STEAP1) emerged as a cancer antigen expressed in various human cancers, including prostate, bladder, colorectal, lung, ovarian, and breast carcinoma and Ewing sarcoma
Several in vitro and in vivo studies revealed that STEAP1-derived peptides are immunogenic and suitable for recognition by cytotoxic T lymphocytes [12,13,14,15,16], indicating that STEAP1 could represent a potential candidate for the development of anticancer vaccines [4, 17]
Summary
Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly upregulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases It shares sequence homology with three enzymes (STEAP2– STEAP4) that catalyze the NADPH-dependent reduction of iron(III). Further indications for a functional heterotrimeric STEAP complex emerged from the recent cryoEM structures of homotrimeric human STEAP4 [29], which revealed a domain-swapped architecture, with the intracellular OxRD positioned beneath the TMD of the adjacent protomer. This arrangement supports a model in which the heme in
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