Structure and Function of the DUF2233 Domain in Bacteria and in the Human Mannose 6-Phosphate Uncovering Enzyme

Abstract

Background: DUF2233 domain is present in bacteria and human UCE, which is implicated in lysosomal storage disorders. Results: Functional residues in DUF2233 and UCE identified in the structure of a bacterial DUF2233 domain were investigated. Conclusion: A function for this domain in bacteria is proposed, and functional residues in human UCE were identified. Significance: This is the first structure/function study of this protein domain.

Three DUF1996 Proteins Localize in Vacuoles and Function in Fungal Responses to Multiple Stresses and Metal Ions

“…A member of the DUF3068 family has been identified as a pore-forming protein that is associated with the passage of hydrophilic solutes in Corynebacterium amycolatum 8 . DUF2233, present in microbial proteins and mammalian transmembrane glycoproteins, has been proven to be essential for the function of the host protein as a phosphodiester glycosidase 9 . A DUF1565 protein (LIC11207) in pathogenic Leptospira strains has been shown to delay polymorphonuclear cell apoptosis and to exert significant antigenicity against human convalescent sera 10 .…”

β‐Strand‐mediated interactions of protein domains

“…Another example of a domain interaction potentially replacing a core β‐strand of a fold exists in the first structural representative from the DUF2233 family (Figure 8A). The crystal structure of protein BACOVA_00430 66 from the human gut bacterium Bacteroides ovatus includes domains from the DUF2233 family present in bacterial and viral proteins, as well as in a homologous family represented by mammalian transmembrane glycoprotein N‐Acetylglucosamine‐1‐phosphodiester α‐N‐acetylglucosaminidase (NAGPA) 66 . The NAGPA enzyme converts N‐acetylglucosamine‐P‐mannose diester to mannose‐6‐P monoester, and disruption of the NAGPA gene has been associated with excessive secretion of acid hydrolases by cells 67 .…”

“…The crystal structure of BACOVA_00430 revealed four domains. The first domain (not included in DUF2233) adopts an α + β fold without clear homologs, followed by three α + β two‐layer DUF2233 domains (possible gene duplications), where the C‐terminal region of the protein is inserted into the second domain 66 . The domain architecture for the NAGPA family suggests that DUF2233 is mobile, as it exists with Copper amine oxidase N‐terminal domain, Calcium‐binding EGF‐like domain, and so forth, in other proteins 68 …”

“…The third DUF2233 domain, along with the N‐terminal domain, forms a continuous β‐sheet comprising seven β‐strands (Figure 8A). The N‐terminal domain structure is similar to proteins from the cystatin/monellin superfamily that contain domains with the cystatin‐like fold, 66 which adopts an α‐helix packed against a curved antiparallel β‐sheet with five strands 69 . DALI structure alignment using the N‐terminal domain identified proteins with the cystatin‐like fold, such as YmpB (PDB 2GU3; DALI Z‐score 5.2) and RAS GTPase‐activating protein (PDB 5FW5; DALI Z‐score 4.8).…”

“…Another protein with a cystatin‐like fold domain is the human latexin protein (Figure 8B), which serves as an endogenous carboxypeptidase inhibitor 70 . This human latexin protein could also be considered as a possible homolog to the N‐terminal cystatin‐like domain in BACOVA_00430 (DALI Z‐score 4.1), 66 and the interaction between the potential N‐terminal cystatin‐like domain and the DUF2233 domain may be replacing the additional strand found in human latexin (Figure 8B). The DUF2233 domain could be considered as a possible homolog to proteins of the NosL/MerB‐like superfamily, which are classified under the same X‐group in ECOD.…”