8i1o

From Proteopedia

Crystal structure of APSK2 domain from human PAPSS2 in complex with exogenous APS and ADP

Structural highlights

8i1o is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PAPS2_HUMAN Defects in PAPSS2 are the cause of spondyloepimetaphyseal dysplasia Pakistani type (SEMD-PA) [MIM:612847. A bone disease characterized by epiphyseal dysplasia with mild metaphyseal abnormalities. Clinical features include short stature evidenced at birth, short and bowed lower limbs, mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee joints. Some patients may manifest premature pubarche and hyperandrogenism associated with skeletal dysplasia and short stature.^[1] ^[2]

Function

PAPS2_HUMAN Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate (PAPS: activated sulfate donor used by sulfotransferase). In mammals, PAPS is the sole source of sulfate; APS appears to be only an intermediate in the sulfate-activation pathway. May have a important role in skeletogenesis during postnatal growth (By similarity).

Publication Abstract from PubMed

Adenosine 5'-phosphosulfate kinase (APSK) catalyzes the rate-limiting biosynthetic step of the universal sulfuryl donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In higher eukaryotes, the APSK and ATP sulfurylase (ATPS) domains are fused in a single chain. Humans have two bifunctional PAPS synthetase isoforms: PAPSS1 with the APSK1 domain and PAPSS2 containing the APSK2 domain. APSK2 displays a distinct higher activity for PAPSS2-mediated PAPS biosynthesis during tumorigenesis. How APSK2 achieves excess PAPS production has remained unclear. APSK1 and APSK2 lack the conventional redox-regulatory element present in plant PAPSS homologs. Here we elucidate the dynamic substrate recognition mechanism of APSK2. We discover that APSK1 contains a species-specific Cys-Cys redox-regulatory element that APSK2 lacks. The absence of this element in APSK2 enhances its enzymatic activity for excess PAPS production and promotes cancer development. Our results help to understand the roles of human PAPSSs during cell development and may facilitate PAPSS2-specific drug discovery.

Redox switching mechanism of the adenosine 5'-phosphosulfate kinase domain (APSK2) of human PAPS synthase 2.,Zhang L, Song W, Li T, Mu Y, Zhang P, Hu J, Lin H, Zhang J, Gao H, Zhang L Structure. 2023 Jul 6;31(7):826-835.e3. doi: 10.1016/j.str.2023.04.012. Epub 2023 , May 18. PMID:37207644^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N, Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten HL, Arlt W. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med. 2009 May 28;360(22):2310-8. doi: 10.1056/NEJMoa0810489. PMID:19474428 doi:10.1056/NEJMoa0810489
↑ Ahmad M, Faiyaz Ul Haque M, Ahmad W, Abbas H, Haque S, Krakow D, Rimoin DL, Lachman RS, Cohn DH. Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred. Am J Med Genet. 1998 Aug 6;78(5):468-73. PMID:9714015
↑ Zhang L, Song W, Li T, Mu Y, Zhang P, Hu J, Lin H, Zhang J, Gao H, Zhang L. Redox switching mechanism of the adenosine 5'-phosphosulfate kinase domain (APSK2) of human PAPS synthase 2. Structure. 2023 May 10:S0969-2126(23)00135-1. PMID:37207644 doi:10.1016/j.str.2023.04.012