Dataset Information

Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition

ABSTRACT: Presequence protease (PreP) degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by airwater interface adsorption, and thereby elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives the rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sheng Li

LAB HEAD: Sheng Li

PROVIDER: PXD029542 | Pride | 2022-05-20

REPOSITORIES: Pride

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Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.

Liang Wenguang G WG Wijaya Juwina J Wei Hui H Noble Alex J AJ Mancl Jordan M JM Mo Swansea S Lee David D Lin King John V JV Pan Man M Liu Chang C Koehler Carla M CM Zhao Minglei M Potter Clinton S CS Carragher Bridget B Li Sheng S Tang Wei-Jen WJ

Nature communications 20220405 1

Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 ...[more]

PMID: 35383169

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			Action	DRS
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	hPrePWT_100000s_B.raw	Raw
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