Birmingham's first will expand the city centre's reach into new catchment areas when it opens next September, according to the woman appointed to manage the operation.
Lisa Williams said the store would help secure Birmingham as a regional powerhouse - and in more than just retail.
The store, alongside the completion of £600 million work at New Street station, forms part of the set to boost the city next year, including the £50 million and
Ms Williams, who is originally from Shirley, said she saw her role as playing a part in attracting people to the region, alongside bosses from the transport and tourism sector.
Work to recruit 650 employees at the new store will begin this autumn.
She said: because it connects the to the
"The flow through those three sites - with us being integral to that in the middle - means it is a great place to be. It links up the city.
"Using the station and getting people to use the rail network to come and visit John Lewis is certainly going to be key as well. We will be serving a local and wider catchment."
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Ms Williams' appointment comes after 25 years climbing the ladder at John Lewis where she is currently head of branch in High Wycombe.
She started working weekends at the Milton Keynes store and served at nine different branches, including under Andy Street, the current managing director and chairman of Greater Birmingham chairman.
But managing the 250,000 sq ft shop will be the biggest challenge yet after John Lewis invested £35 million in the store - but it is one she is excited by.
She said: "I've spent a lot of time out of Birmingham but it has always been where my heart is.
"It is where my family are and my network is and it has always been an intention to get back here. This is perfect for that."
She added: "Being a Brummie and campaigning with a Brummie managing director in Andy Street, I have been badgering for this for 25 years.
"So it is not just a shop for me, it is a dream I hoped would happen for a long time. This is the Second City - why would we not be here?"
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Ms Williams accepts John Lewis has a major part to play in the renaissance of Birmingham city centre and committed to working with the local community and businesses.
Next year will be key from a retail perspective but the Midland Metro and a £26 million redevelopment at the are also major milestones.
Ms Williams added: "We see this as a regional flagship and John Lewis will be putting everything behind that.
"We don't just land in a city and trade. You will see a lot of community work that we will get involved with because that is absolutely what we do as a brand.
"It is about using me and my team as it develops to get out into the community to give something back.
"We will start to build strong relationships in the city centre, that is my job primarily, and try to get Greater Birmingham recognised.
"And it might not just be retail - it could be the theatre or the airport - but we want people coming in and having a great experience in Birmingham."
Work to recruit staff for the new store will begin in a matter of months and the roles on offer will include visual merchandising, sales, maintenance and management positions.
The company signed a jobs and skills charter with Birmingham City Council and Network Rail earlier this year pledging to help local people access more than 1,000 new jobs created by the entire development.
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